Substituted imidazopyridines as hdm2 inhibitors

ABSTRACT

The present invention provides substituted imidazopyridines as described herein or a pharmaceutically acceptable salt or solvate thereof. The representative compounds are useful as inhibitors of the HDM2 protein. Also disclosed are pharmaceutical compositions comprising the above compounds and potential methods of treating cancer using the same.

FIELD OF THE INVENTION

The present invention relates to novel compounds useful as Human DoubleMinute 2 (“HDM2”) protein inhibitors, regulators or modulators,pharmaceutical compositions containing the compounds and potentialmethods of treatment using the compounds and compositions to potentiallytreat diseases such as, for example, cancer, diseases involving abnormalcell proliferation, and diseases caused by inadequate p53 levels.

BACKGROUND OF THE INVENTION

The tumor suppressor protein p53 plays a central role in maintaining theintegrity of the genome in a cell by regulating the expression of adiverse array of genes responsible for DNA repair, cell cycle and growtharrest, and apoptosis [May et al., Oncogene 18 (53) (1999) p. 7621-7636;Oren, Cell Death Differ. 10 (4) (2003) p. 431-4-[2, Hall and Peters,Adv. Cancer Res., 68: (1996) p. 67-108; Hainaut et al., Nucleic AcidRes., 25: (1997) p. 151-157; Sherr, Cancer Res., 60: (2000) p. 3689-95].In response to oncogenic stress signals, the cell triggers the p53transcription factor to activate genes implicated in the regulation cellcycle, which thereby initiates either apoptosis or cell cycle arrest.Apoptosis facilitates the elimination of damaged cells from theorganism, while cell cycle arrest enables damaged cells to repairgenetic damage [reviewed in Ko et al., Genes & Devel. 10: (1996) p.1054-1072; Levine, Cell 88: (1997) p. 323-331]. The loss of thesafeguard functions of p53 predisposes damaged cells to progress to acancerous state. Inactivating p53 in mice consistently leads to anunusually high rate of tumors [Donehower et al., Nature, 356: (1992) p.215-221].

The p53 transcription factor promotes the expression of a number of cellcycle regulatory genes, including its own negative regulator, the geneencoding the Mouse Double Minute 2 (MDM2) protein [Chene, Nature ReviewsCancer 3: (2003) p. 102-109; Momand, Gene 242 (1-2): (2000) p. 15-29;Zheleva et al. Mini. Rev. Med. Chem. 3 (3): (2003) p. 257-270]. The MDM2protein (designated HDM2 in humans) acts to down-regulate p53 activityin an auto-regulatory manner [Wu et al, Genes Dev., 7: (1993) p.1126-1132; Bairak et al., EMBO J, 12: (1993) p. 461-468]. In the absenceof oncogenic stress signals, i.e., under normal cellular conditions, theMDM2 protein serves to maintain p53 activity at low levels [Wu et al,Genes Dev., 7: (1993) p. 1126-1132; Barak et al., EMBO J, 12: (1993) p.461-468]. However, in response to cellular DNA damage or under cellularstress, p53 activity increases helping to prevent the propagation ofpermanently damaged clones of cells by induction of cell cycle andgrowth arrest or apoptosis.

The regulation of p53 function relies on an appropriate balance betweenthe two components of this p53-MDM2 auto-regulatory system. Indeed, thisbalance appears to be essential for cell survival. There are at leastthree ways that MDM2 acts to down-regulate p53 activity. First, MDM2 canbind to the N-terminal transcriptional activation domain of p53 to blockexpression of p53-responsive genes [Kussie et al., Science, 274: (1996)p. 948-953; Oliner et al., Nature, 362: (1993) p. 857-860; Momand et al,Cell, 69: (1992) p. 1237-1245]. Second, MDM2 shuttles p53 from thenucleus to the cytoplasm to facilitate the proteolytic degradation ofp53 [Roth et al, EMBO J, 17: (1998) p. 554-564; Freedman et al., MolCell Biol, 18: (1998) p. 7288-7293; Tao and Levine, Proc. Natl. Acad.Sci. 96: (1999) p. 3077-3080]. Finally, MDM2 possesses an intrinsic E3ligase activity for conjugating ubiquitin to p53 for degradation withinthe ubiquitin-dependent 26S proteosome pathway [Honda et al., FEBS Lett,420: (1997) p. 25-27; Yasuda, Oncogene 19: (2000) p. 1473-1476]. Thus,MDM2 impedes the ability of the p53 transcription factor to promote theexpression of its target genes by binding p53 in the nucleus.Attenuating the p53-MDM2 auto-regulatory system can have a criticaleffect on cell homeostasis. Consistently, a correlation between theoverexpression of MDM2 and tumor formation has been reported [Chene,Nature 3: (2003) p. 102-109]. Functional inactivation of wild type p53is found in many types of human tumors. Restoring the function of p53 intumor cells by anti-MDM2 therapy would result in slowing the tumorproliferation and instead stimulate apoptosis. Not surprisingly then,there is currently a substantial effort being made to identify newanticancer agents that hinder the ability of HDM2 to interact with p53[Chene, Nature 3: (2003) p. 102-109]. Antibodies, peptides, andantisense oligonucleotides have been demonstrated to destroy thep53-MDM2 interaction, which would release p53 from the negative controlof MDM2, leading to activation of the p53 pathway allowing the normalsignals of growth arrest and/or apoptosis to function, which offers apotential therapeutic approach to treating cancer and other diseasescharacterized by abnormal cell proliferation. [See, e.g., Blaydes etal., Oncogene 14: (1997) p. 1859-1868; Bottger et al., Oncogene 13 (10):(1996) p. 2141-2147].

Small molecules, said to antagonize the p53-MDM2 interaction, have beendescribed. WO 00/15657 (Zeneca Limited) describes piperizine-4-phenylderivatives as inhibitors of the interaction between MDM2 and p53.Grasberger et al. (J. Med. Chem., 48 (2005) p. 909-912) (Johnson &Johnson Pharmaceutical Research & Development L.L.C.) describesdiscovery and co-crystal structure of benzodiazepinedione as HDM2antagonists that activate p53 in cells. Galatin et al. (J. Med. Chem. 47(2004) p. 4163-4165) describes a nonpeptidic sulfonamide inhibitor ofthe p53-MDM2 interaction and activator of p53 dependent transcription inMDM2-overexpressing cells.

U.S. Pub. No. 2004/0259867 A1 and 2004/0259884 A1 describesCis-imidazoles (Hoffmann La Roche Inc.) and WO2005/110996A1 and WO03/051359 describes Cis-Imidazolines (Hoffmann La Roche Inc.) ascompounds that inhibit the interaction of MDM2 with p53-like peptidesresulting in antiproliferation. WO 2004/080460 A1 describes substitutedpiperidine compounds as MDM2-p53 inhibitors for treating cancer(Hoffmann La Roche Inc.). EP 0947494 A1 describes phenoxy acetic acidderivatives and phenoxy methyltetrazole that act as antagonists of MDM2and interfere with the protein-protein interaction between MDM2 and p53,which results in anti-tumor properties (Hoffmann La Roche Inc.). Duncanet al., J. Am. Chem. Soc. 123 (4): (2001) p. 554-560 describes ap-53-MDM2 antagonist, chlorofusin, from a Fusarium Sp. Stoll et al.,Biochemistry 40 (2) (2001) p. 336-344 describes chalcone derivativesthat antagonize interactions between the human oncoprotein MDM2 and p53.

There is a need for effective inhibitors of the HDM2 or MDM2 protein inorder to treat or prevent cancer, other disease states associated withcell proliferation, diseases associated with HDM2, or diseases caused byinadequate p53 activity. The present application discloses compoundsthat have potency in inhibiting or antagonizing the HDM2-p53 andMDM2-p53 interaction and/or activating p53 proteins in cells.

In its many embodiments, the present invention provides novel compoundshaving HDM2 or MDM2 antagonist activity, methods of preparing suchcompounds, pharmaceutical compositions comprising one or more of suchcompounds, methods of preparing pharmaceutical formulations comprisingone or more of such compounds, potential methods of treatment orprevention of one or more diseases associated with HDM2, MDM2, p53, orp53 peptides by administering such compounds or pharmaceuticalcompositions.

SUMMARY OF THE INVENTION

In its many embodiments, the present invention provides a novel class ofsubstituted imidazopyridine compounds, pharmaceutical compositionscomprising one or more said compounds, and potential methods for usingsaid compounds for treating or preventing a disease associated with theHDM2 protein.

Accordingly, in one aspect the present invention provides a compound ofFormula I:

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention provides compounds illustratedas Formula I, as described above, or pharmaceutically acceptable saltsor solvates thereof. Accordingly, in one aspect the present inventionprovides a compound of Formula I:

Wherein

R¹ is selected from the group consisting of H, C₁-C₆alkyl, —(CR^(a)₂)_(n)COOR¹¹, -T-NHR⁵, —(CR^(a) ₂)_(n)NR⁵SO₂R⁶, —(CR^(a) ₂)_(n)SO₂NR⁵R⁶,—(CR^(a) ₂)_(n)C(O)NR^(c)SO₂N(R^(c))₂, —(CR^(a)₂)_(n)C(O)NR^(c)SO₂R^(c), —(CR^(a) ₂)_(n)C(O)R⁵, —(CR^(a) ₂)_(n)CONR⁵R⁶,—(CR^(a) ₂)_(n)CONR⁵OR⁶, —(CR^(a) ₂)_(n)NR⁵C(O)R⁶, —(CR^(a) ₂)_(n)OR⁵,—(CR^(a) ₂)_(n)S(O)R^(c), —(CR^(a) ₂)_(n)S(O)₂R^(c), and nitrogencontaining 5 or 6-membered heterocyclic, heteroaryl or heterocyclenylring, wherein the alkyl and 5 or 6-membered ring can be optionallysubstituted with OR^(c), SR^(c), NH₂, nitro, CN, amide, COOR¹¹,C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, C₁-C₆hydroxyalkyl,C₂-C₆alkenyl, C₁-C₆alkyl-C(═O)O—, C₁-C₆alkyl-C(═O)—, C₂-C₆alkynyl, halogroup, hydroxyalkoxy, —SO₂NR^(c)R^(c), —NR^(c)SO₂R^(c),C₁-C₆alkylsulfonyl, C₁-C₆alkylamino or di(C₁-C₆)alkylamino;R² is selected from the group consisting of aryl, heteroaryl,C₃-C₈cycloalkyl, —W—(CR^(a)R⁹)_(t)R⁷, and heterocyclic, wherein W isNR^(c) or O, wherein the aryl, heteroaryl, or heterocyclic is optionallysubstituted with R¹² selected from the group consisting of halo, CN,haloC₁-C₆alkyl, C₁-C₆alkyl, —(CR^(a) ₂)_(z)OR^(c), —(CR^(a) ₂)_(z)NHR⁸,—(CR^(a) ₂)_(z)C(O)NR^(c)R^(c), —(CR^(a) ₂)_(z)COOR¹⁰, —(CR^(a)₂)_(z)aryl, —(CR^(a) ₂)_(z)heteroaryl, —(CR^(a) ₂)_(z)heterocyclic,—(CR^(a) ₂)_(z)C₃-C₈cycloalkyl, —(CR^(a) ₂)_(z)cyclenyl, and —(CR^(a)₂)_(z)heterocyclenyl, wherein the alkyl, aryl, heteroaryl, heterocyclic,cycloalkyl, cyclenyl and heterocyclenyl of R¹² can be optionallysubstituted with OH, NH₂, nitro, CN, CON(R^(c))₂, —(CR^(a) ₂)_(z)COOR¹⁰,C₁-C₆alkoxy, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆haloalkoxy,C₁-C₆hydroxyalkyl, C₂-C₆alkenyl, C₁-C₆alkyl-C(═O)O—, C₁-C₆alkyl-C(═O)—,C₂-C₆alkynyl, halo group, hydroxyalkoxy, —SO₂NR^(c)R^(c),—NR^(c)SO₂R^(c), C₁-C₆alkylsulfonyl, C₁-C₆alkylamino ordi(C₁-C₆)alkylamino;R³ is selected from the group consisting of H, —(CR^(a) ₂)_(q)NR^(c)R⁸,—(CR^(a) ₂)_(q)OR⁸, —(CR^(a) ₂)_(q)SR⁸, —(CR^(a) ₂)_(q)C(O)R⁸, —(CR^(a)₂)_(q)S(O)R⁸, —(CR^(a) ₂)_(q)S(O)₂R⁸, —(CR^(a) ₂)_(q)CONR^(c)R⁸,—(CR^(a) ₂)_(q)NR^(c)C(O)R⁸, -T-alkyl, C₂-C₆alkenyl, -T-aryl,-T-heteroaryl, -T-heterocyclic, -T-C₃-C₇cycloalkyl, -T-cyclenyl, and-T-heterocyclenyl,wherein the alkyl, alkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl,cyclenyl and heterocyclenyl can be optionally substituted with halo,SR^(c), OR^(c), haloC₁-C₆alkyl, haloC₁-C₆alkoxy, —(CR^(a) ₂)_(z)CN,C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —(CR^(a) ₂)_(z)C(O)OR¹¹,—(CR^(a) ₂)_(z)C(O)R⁸, —(CR^(a) ₂)_(z)OR⁸, —(CR^(a) ₂)_(z)NR^(c)R⁸,—(CR^(a) ₂)_(z)S(O)₂R⁸, —(CR^(a) ₂)_(z)C(O)NR^(c)R⁸, —(CR^(a)₂)_(z)aryl, —(CR^(a) ₂)_(z)heteroaryl, —(CR^(a) ₂)_(z)C₃-C₈cycloalkyl,—(CR^(a) ₂)_(z)heterocyclic, —(CR^(a) ₂)_(z)heterocyclenyl, —(CR^(a)₂)_(z)cyclenyl, —(CR^(a) ₂)_(z)SO₂NR^(c)R⁸, or —(CR^(a) ₂)_(z)O(CR^(a)₂)_(z)Y(CR^(a) ₂),U,said alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl,heterocyclic, heterocyclenyl and cyclenyl can further be substitutedwith OH, SH, NH₂, nitro, CN, CON(R^(c))₂, COOR¹⁰, C₁-C₆alkoxy,C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl, C₁-C₆haloalkoxy,C₁-C₆hydroxyalkyl, C₁-C₆alkyl-C(═O)O—, C₁-C₆alkyl-C(═O)—, C₂-C₆alkynyl,halo group, hydroxyalkoxy, —SO₂NR^(c)R^(c), —SO₂R^(c), —NR^(c)SO₂R^(c),C₁-C₆alkylsulfonyl, C₁-C₆alkylamino or di(C₁-C₆)alkylamino;R⁴ is selected from the group consisting of C₁-C₆alkyl, —(CR^(a)₂)_(m)aryl, —(CR^(a) ₂)_(m)heteroaryl, —(CR^(a) ₂)_(m)heterocyclic,—(CR^(a) ₂)_(m)C₃-C₈cycloalkyl, —(CR^(a) ₂)_(m)cyclenyl, and —(CR^(a)₂)_(m)heterocyclenyl, wherein the alkyl, aryl, heteroaryl, heterocyclic,cycloalkyl, cyclenyl, and heterocyclenyl can be optionally substitutedwith OH, SH, NH₂, nitro, CN, CON(R^(c))₂, COOR¹¹, C₁-C₆alkoxy,C₁-C₆alkyl, C₃-C₆cycloalkyl, haloC₂-C₆alkenyl, C₂-C₆alkenyl,C₂-C₆alkenoxy, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, C₁-C₆hydroxyalkyl,C₁-C₆alkyl-C(═O)O—, C₁-C₆alkyl-C(═O)—, C₂-C₆alkynyl, halo group,hydroxyalkoxy, —SO₂NR^(c)R^(c), —NR^(c)SO₂R^(c), C₁-C₆alkylsulfonyl,C₁-C₆alkylamino or di(C₁-C₆)alkylamino;R⁵ is independently selected from the group consisting of H, C₁-C₆alkyl,—C₀-C₆alkyl-C₃-C₈cycloalkyl, —C₀-C₆alkyl-heteroaryl, —C₀-C₆alkyl-aryl,and —C₀-C₆alkylheterocyclic, wherein the alkyl, cycloalkyl, heteroaryl,aryl, and heterocyclic can be optionally substituted with C₂-C₃alkenyl,C₃-C₆cycloalkyl, C₁-C₃alkoxy, OH, halo, NH₂, C₁-C₃alkylamino,C₁-C₃dialkylamino or COOR¹¹;R⁶ is independently selected from the group consisting of H, C₁-C₆alkyl,—C₀-C₆alkyl-C₃-C₈cycloalkyl, —C₀-C₆alkyl-heteroaryl, —C₀-C₆alkyl-aryl,and —C₀-C₆alkylheterocyclic, wherein the alkyl, cycloalkyl, heteroaryl,aryl, and heterocyclic can be optionally substituted with C₂-C₃alkenyl,C₃-C₆cycloalkyl, C₁-C₃alkoxy, OH, halo, NH₂, C₁-C₃alkylamino,C₁-C₃dialkylamino or COOR¹¹;R⁷ is selected from the group consisting of H, C₁-C₆alkyl, C₂-C₆alkenyl,C₃-C₈cycloalkyl, aryl, heteroaryl, heterocyclic, wherein the alkyl,alkenyl, cycloalkyl, aryl, heteroaryl or heterocyclic can be optionallysubstituted with halo, nitro, CN, C₁-C₆haloalkyl, C₁-C₆haloalkoxy,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkyl, —C₀-C₆alkyl-C₃-C₈cycloalkyl,—C₀-C₆alkyl-heteroaryl, —C₀-C₆alkyl-aryl, —C₀-C₆alkylheterocyclic,—C₀-C₆alkylheterocyclenyl, —C₀-C₆alkylcyclenyl, —(CR^(a) ₂)_(z)NR⁶R⁶,—(CR^(a) ₂)_(z)NR⁶SO₂R⁶, —(CR^(a) ₂)_(z)SO₂NR⁶R⁶, —(CR^(a) ₂)_(z)C(O)R⁶,—(CR^(a) ₂)_(z)C(O)OR¹⁹, —(CR^(a) ₂)_(z)CONR⁶R⁶, —(CR^(a)₂)_(z)CONR⁵OR⁶, —(CR^(a) ₂)_(z)NR⁵C(O)R⁶, —(CR^(a) ₂)_(z)OR⁵, —(CR^(a)₂)_(z)S(O)R^(c), and —(CR^(a) ₂)_(z)S(O)₂R^(c);R⁸ is independently selected from the group consisting of H, —(CR^(a)₂)_(s)-heteroaryl, —(CR^(a) ₂)_(s)-aryl, —(CR^(a) ₂)_(s)-heterocyclic,—(CR^(a) ₂)_(s)-heterocyclenyl, —(CR^(a) ₂)_(s)-cyclenyl, —(CR^(a)₂)_(s)C₃-C₇cycloalkyl, and C₁-C₆alkyl, wherein the heteroaryl, aryl,heterocyclic, heterocyclenyl, cyclenyl, cycloalkyl, and alkyl can beoptionally substituted with OH, NH₂, nitro, CN, CON(R^(c))₂, COOR¹¹,C₁-C₆alkoxy, C₁-C₆alkyl, C₂-C₆alkenyl, heterocyclic, C₁-C₆haloalkyl,C₁-C₆haloalkoxy, C₁-C₆hydroxyalkyl, C₁-C₆alkyl-C(═O)O—,C₁-C₆alkyl-C(═O)—, C₂-C₆alkynyl, halo group, hydroxyalkoxy,—SO₂NR^(c)R^(c), —NR^(c)SO₂R^(c), C₁-C₆alkylsulfonyl, C₁-C₆alkylamino ordi(C₁-C₆)alkylamino;R⁹ is independently selected from the group consisting of H, C₁-C₆alkyl,C₁-C₆haloalkyl, C₃-C₈cycloalkyl, aryl, heteroaryl, and heterocyclic,wherein the alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic can beoptionally substituted with —C₀-C₆alkylOR^(c), —C₀-C₆alkylN(R^(c))₂,COOR¹⁹, nitro, CN, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆haloalkoxy,C₁-C₆hydroxyalkyl, C₂-C₆alkenyl, C₁-C₆alkyl-C(═O)O—, C₁-C₆alkyl-C(═O)—,C₂-C₆alkynyl, halo group, hydroxyalkoxy, —SO₂NR^(c)R^(c),—NR^(c)SO₂R^(c), C₁-C₆alkylsulfonyl, heterocyclic, or C(O)NHR^(c);R¹⁰ is independently selected from the group consisting of C₁-C₆alkyl,—(CR^(c) ₂)_(z)C₃-C₈cycloalkyl, —(CR^(c) ₂)_(z)heteroaryl, —(CR^(c)₂)_(z)aryl, and —(CR^(c) ₂)_(z)heterocyclic, wherein the heteroaryl,aryl, heterocyclic, cycloalkyl and alkyl can be optionally substitutedwith C₁-C₆alkyl, OH, halo, or haloC₁-C₆alkyl;

R¹¹ is independently selected from the group consisting of H,C₁-C₆alkyl, —(CR^(c) ₂)_(z)C₃-C₈cycloalkyl, —(CR^(c) ₂)_(z)heteroaryl,—(CR^(c) ₂)_(z)aryl, and —(CR^(c) ₂)_(z)heterocyclic wherein theheteroaryl, aryl, heterocyclic, cycloalkyl and alkyl can be optionallysubstituted with C₁-C₆alkyl, C₁-C₆alkoxy, OH, halo, or haloC₁-C₆alkyl;

R¹⁷ is independently selected from the group consisting of H, halo,COOH, oxadiazolone, C₁-C₆alkyl, C₁-C₆alkoxy, NR^(c)R^(c), —(CR^(c)₂)_(z)C₃-C₈cycloalkyl, —(CR^(c) ₂)_(z)heteroaryl, —(CR^(c) ₂)_(z)aryl,and —(CR^(c) ₂)_(z)heterocyclic wherein the heteroaryl, aryl,heterocyclic, cycloalkyl and alkyl can be optionally substituted withC₁-C₆alkyl, OH, halo, or haloC₁-C₆alkyl;R^(a) is independently H, C(O)NR^(c) ₂, OR^(c), NH₂, halo, C₁-C₆alkyl,or C₂-C₆alkenyl, said alkyl or alkenyl is optionally substituted withOH, C₁-C₄alkoxy, NH₂, halo, haloC₁-C₄alkyl, C₃-C₆cycloalkyl, orC₂-C₄alkenyl;R^(c) is independently H or C₁-C₄alkyl optionally substituted withC₂-C₃alkenyl, C₃-C₆cycloalkyl, C₁-C₃alkoxy, OH, halo, NH₂,C₁-C₃alkylamino, or C₁-C₃dialkylamino;T is independently C₂-C₃alkenyl, —C(O)—, —(CR^(a) ₂)_(q)—, —C(═CH₂)—,—(CR^(a) ₂)_(q)—C(═CH₂)—, —C(═CH₂)—(CR^(a) ₂)_(q)—, —C(═NH)—, —(CR^(a)₂)_(q)—C(═NH)—, or —C(═NH₂)—(CR^(a) ₂)_(q)—;Y is a bond, —C(O)NR^(c)—, —NR^(c)C(O)—, or —NR^(c)—;U is H, COOR¹¹, OH, heteroaryl or heterocyclic;n is independently 0, 1, 2 or 3;m is independently 0, 1 or 2;q is independently 0, 1, 2, or 3;s is independently 0, 1 or 2;t is independently 0, 1, or 2;v is independently 1, 2, 3 or 4;z is independently 0, 1, 2, 3 or 4;or a pharmaceutically acceptable salt thereof.

The present invention also provides the following compounds underFormula I:

Wherein

R¹ is selected from the group consisting of H, C₁-C₆alkyl, —(CR^(a)₂)_(n)COOR¹¹, -T-NHR⁵, —(CR^(a) ₂)_(n)NR⁵SO₂R⁶, —(CR^(a) ₂)_(n)SO₂NR⁵R⁶,—(CR^(a) ₂)_(n)C(O)NR^(c)SO₂N(R^(c))₂, —(CR^(a)₂)_(n)C(O)NR^(c)SO₂R^(c), —(CR^(a) ₂)_(n)C(O)R⁵, —(CR^(a) ₂)_(n)CONR⁵R⁶,—(CR^(a) ₂)_(n)CONR⁵OR⁶, —(CR^(a) ₂)_(n)NR⁵C(O)R⁶, —(CR^(a) ₂)_(n)OR⁵,—(CR^(a) ₂)_(n)S(O)R^(c), —(CR^(a) ₂)_(n)S(O)₂R^(c), and nitrogencontaining 5 or 6-membered heterocyclic, heteroaryl or heterocyclenylring, wherein the alkyl and 5 or 6-membered ring can be optionallysubstituted with OR^(c), SR^(c), NH₂, nitro, CN, amide, COOR¹¹,C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, C₁-C₆hydroxyalkyl,C₂-C₆alkenyl, C₁-C₆alkyl-C(═O)O—, C₁-C₆alkyl-C(═O)—, C₂-C₆alkynyl, halogroup, hydroxyalkoxy, —SO₂NR^(c)R^(c), —NR^(c)SO₂R^(c),C₁-C₆alkylsulfonyl, C₁-C₆alkylamino or di(C₁-C₆)alkylamino;R² is selected from the group consisting of aryl, heteroaryl,—W—(CR^(a)R⁹)_(t)R⁷, and heterocyclic, wherein W is NR^(C) or O, whereinthe aryl, heteroaryl, or heterocyclic is optionally substituted with R¹²selected from the group consisting of halo, CN, haloC₁-C₆alkyl,C₁-C₆alkyl, —(CR^(a) ₂)_(z)OR^(c), —(CR^(a) ₂)_(z)NHR⁸, —(CR^(a)₂)_(z)C(O)NR^(c)R^(c), —(CR^(a) ₂)_(z)aryl, —(CR^(a) ₂)_(z)heteroaryl,—(CR^(a) ₂)_(z)heterocyclic, —(CR^(a) ₂)_(z)C₃-C₈cycloalkyl, —(CR^(a)₂)_(z)cyclenyl, and —(CR^(a) ₂)_(z)heterocyclenyl, wherein the alkyl,aryl, heteroaryl, heterocyclic, cycloalkyl, cyclenyl and heterocyclenylof R¹² can be optionally substituted with OH, NH₂, nitro, CN,CON(R^(c))₂, —(CR^(a) ₂)_(z)COOR¹⁰, C₁-C₆alkoxy, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆haloalkoxy, C₁-C₆hydroxyalkyl, C₂-C₆alkenyl,C₁-C₆alkyl-C(═O)O—, C₁-C₆alkyl-C(═O)—, C₂-C₆alkynyl, halo group,hydroxyalkoxy, —SO₂NR^(c)R^(c), —NR^(c)SO₂R^(c), C₁-C₆alkylsulfonyl,C₁-C₆alkylamino or di(C₁-C₆)alkylamino;R³ is selected from the group consisting of H, —(CR^(a) ₂)_(q)NR^(c)R⁸,—(CR^(a) ₂)_(q)OR⁸, —(CR^(a) ₂)_(q)SR⁸, —(CR^(a) ₂)_(q)C(O)R⁸, —(CR^(a)₂)_(q)S(O)R⁸, —(CR^(a) ₂)_(q)S(O)₂R⁸, —(CR^(a) ₂)_(q)CONR^(c)R⁸,—(CR^(a) ₂)_(q)NR^(c)C(O)R⁸, -T-alkyl, C₂-C₆alkenyl, -T-aryl,-T-heteroaryl, -T-heterocyclic, -T-C₃-C₇cycloalkyl, -T-cyclenyl, and-T-heterocyclenyl,wherein the alkyl, alkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl,cyclenyl and heterocyclenyl can be optionally substituted with halo,OR^(c), haloC₁-C₆alkyl, haloC₁-C₆alkoxy, —(CR^(a) ₂)_(z)CN, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, —(CR^(a) ₂)_(z)C(O)OR¹¹, —(CR^(a)₂)_(z)C(O)R⁸, —(CR^(a) ₂)_(z)OR⁸, —(CR^(a) ₂)_(z)NR^(c)R⁸, —(CR^(a)₂)_(z)S(O)₂R⁸, —(CR^(a) ₂)_(z)C(O)NR^(c)R⁸, —(CR^(a) ₂)_(z)aryl,—(CR^(a) ₂)_(z)heteroaryl, —(CR^(a) ₂)_(z)C₃-C₈cycloalkyl, —(CR^(a)₂)_(z)heterocyclic, —(CR^(a) ₂)_(z)heterocyclenyl, —(CR^(a)₂)_(z)cyclenyl, —(CR^(a) ₂)_(z)SO₂NR^(c)R⁸, or —(CR^(a) ₂)_(z)O(CR^(a)₂)_(z)Y(CR^(a) ₂)_(z)U,said alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl,heterocyclic, heterocyclenyl and cyclenyl can further be substitutedwith OH, NH₂, nitro, CN, CON(R^(c))₂, COOR¹⁰, C₁-C₆alkoxy, C₁-C₆alkyl,C₂-C₆alkenyl, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, C₁-C₆hydroxyalkyl,C₁-C₆alkyl-C(═O)O—, C₁-C₆alkyl-C(═O)—, C₂-C₆alkynyl, halo group,hydroxyalkoxy, —SO₂NR^(c)R^(c), —NR^(c)SO₂R^(c), C₁-C₆alkylsulfonyl,C₁-C₆alkylamino or di(C₁-C₆)alkylamino;R⁴ is selected from the group consisting of C₁-C₆alkyl, —(CR^(a)₂)_(m)aryl, —(CR^(a) ₂)_(m)heteroaryl, —(CR^(a) ₂)_(m)heterocyclic,—(CR^(a) ₂)_(m)C₃-C₈cycloalkyl, —(CR^(a) ₂)_(m)cyclenyl, and —(CR^(a)₂)_(m)heterocyclenyl, wherein the alkyl, aryl, heteroaryl, heterocyclic,cycloalkyl, cyclenyl, and heterocyclenyl can be optionally substitutedwith OH, SH, NH₂, nitro, CN, CON(R^(c))₂, COOR¹¹, C₁-C₆alkoxy,C₁-C₆alkyl, C₃-C₆cycloalkyl, haloC₂-C₆alkenyl, C₂-C₆alkenyl,C₂-C₆alkenoxy, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, C₁-C₆hydroxyalkyl,C₁-C₆alkyl-C(═O)O—, C₁-C₆alkyl-C(═O)—, C₂-C₆alkynyl, halo group,hydroxyalkoxy, —SO₂NR^(c)R^(c), —NR^(c)SO₂R^(c), C₁-C₆alkylsulfonyl,C₁-C₆alkylamino or di(C₁-C₆)alkylamino;R⁵ is independently selected from the group consisting of H, C₁-C₆alkyl,—C₀-C₆alkyl-C₃-C₈cycloalkyl, —C₀-C₆alkyl-heteroaryl, —C₀-C₆alkyl-aryl,and —C₀-C₆alkylheterocyclic, wherein the alkyl, cycloalkyl, heteroaryl,aryl, and heterocyclic can be optionally substituted with C₂-C₃alkenyl,C₃-C₆cycloalkyl, C₁-C₃alkoxy, OH, halo, NH₂, C₁-C₃alkylamino,C₁-C₃dialkylamino or COOR¹¹;R⁶ is independently selected from the group consisting of H, C₁-C₆alkyl,—C₀-C₆alkyl-C₃-C₈cycloalkyl, —C₀-C₆alkyl-heteroaryl, —C₀-C₆alkyl-aryl,and —C₀-C₆alkylheterocyclic, wherein the alkyl, cycloalkyl, heteroaryl,aryl, and heterocyclic can be optionally substituted with C₂-C₃alkenyl,C₃-C₆cycloalkyl, C₁-C₃alkoxy, OH, halo, NH₂, C₁-C₃alkylamino,C₁-C₃dialkylamino or COOR¹¹;R⁷ is selected from the group consisting of H, C₁-C₆alkyl, C₂-C₆alkenyl,C₃-C₈cycloalkyl, aryl, heteroaryl, heterocyclic, wherein the alkyl,alkenyl, cycloalkyl, aryl, heteroaryl or heterocyclic can be optionallysubstituted with halo, nitro, CN, C₁-C₆haloalkyl, C₁-C₆haloalkoxy,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkyl, —C₀-C₆alkyl-C₃-C₈cycloalkyl,—C₀-C₆alkyl-heteroaryl, —C₀-C₆alkyl-aryl, —C₀-C₆alkylheterocyclic,—C₀-C₆alkylheterocyclenyl, —C₀-C₆alkylcyclenyl, —(CR^(a) ₂)_(z)NR⁵R⁶,—(CR^(a) ₂)_(z)NR⁵SO₂R⁶, —(CR^(a) ₂)_(z)SO₂NR⁵R⁶, —(CR^(a) ₂)_(z)C(O)R⁵,—(CR^(a) ₂)_(z)C(O)OR¹⁰, —(CR^(a) ₂)_(z)CONR⁵R⁶, —(CR^(a)₂)_(z)CONR⁵OR⁶, —(CR^(a) ₂)_(z)NR⁵C(O)R⁶, —(CR^(a) ₂)_(z)OR⁵, —(CR^(a)₂)_(z)S(O)R^(c), and —(CR^(a) ₂)_(z)S(O)₂R^(c);R⁸ is independently selected from the group consisting of H, —(CR^(a)₂)_(s)-heteroaryl, —(CR^(a) ₂)_(s)-aryl, —(CR^(a) ₂)_(s)-heterocyclic,—(CR^(a) ₂)_(s)-heterocyclenyl, —(CR^(a) ₂)_(s)-cyclenyl, —(CR^(a)₂)_(s)C₃-C₇cycloalkyl, and C₁-C₆alkyl, wherein the heteroaryl, aryl,heterocyclic, heterocyclenyl, cyclenyl, cycloalkyl, and alkyl can beoptionally substituted with OH, NH₂, nitro, CN, CON(R^(c))₂, COOR¹¹,C₁-C₆alkoxy, C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl, C₁-C₆haloalkoxy,C₁-C₆hydroxyalkyl, C₁-C₆alkyl-C(═O)O—, C₁-C₆alkyl-C(═O)—, C₂-C₆alkynyl,halo group, hydroxyalkoxy, —SO₂NR^(c)R^(c), —NR^(c)SO₂R^(c),C₁-C₆alkylsulfonyl, C₁-C₆alkylamino or di(C₁-C₆)alkylamino;R⁹ is independently selected from the group consisting of H, C₁-C₆alkyl,C₁-C₆haloalkyl, C₃-C₈cycloalkyl, aryl, heteroaryl, and heterocyclic,wherein the alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic can beoptionally substituted with —C₀-C₆alkylOR^(c), —C₀-C₆alkylN(R^(c))₂,COOR¹⁹, nitro, CN, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆haloalkoxy,C₁-C₆hydroxyalkyl, C₂-C₆alkenyl, C₁-C₆alkyl-C(═O)O—, C₁-C₆alkyl-C(═O)—,C₂-C₆alkynyl, halo group, hydroxyalkoxy, —SO₂NR^(c)R^(c),—NR^(c)SO₂R^(c), C₁-C₆alkylsulfonyl, heterocyclic, or C(O)NHR^(c);R¹⁰ is independently selected from the group consisting of C₁-C₆alkyl,—(CR^(c) ₂)_(z)C₃-C₈cycloalkyl, —(CR^(c) ₂)_(z)-heteroaryl, —(CR^(c)₂)_(z)-aryl, and —(CR^(c) ₂)_(z)-heterocyclic, wherein the heteroaryl,aryl, heterocyclic, cycloalkyl and alkyl can be optionally substitutedwith C₁-C₆alkyl, OH, halo, or haloC₁-C₆alkyl;R¹¹ is independently selected from the group consisting of H,C₁-C₆alkyl, —(CR^(c) ₂)_(z)C₃-C₈cycloalkyl, —(CR^(c) ₂)_(z)heteroaryl,—(CR^(c) ₂)_(z)aryl, and —(CR^(c) ₂)_(z)heterocyclic wherein theheteroaryl, aryl, heterocyclic, cycloalkyl and alkyl can be optionallysubstituted with C₁-C₆alkyl, OH, halo, or haloC₁-C₆alkyl;

R¹⁷ is independently selected from the group consisting of H, halo,COOH, oxadiazolone, C₁-C₆alkyl, —(CR^(c) ₂)_(z)C₃-C₈cycloalkyl, —(CR^(c)₂)_(z)heteroaryl, —(CR^(c) ₂)_(z)aryl, and —(CR^(c) ₂)_(z)heterocyclicwherein the heteroaryl, aryl, heterocyclic, cycloalkyl and alkyl can beoptionally substituted with C₁-C₆alkyl, OH, halo, or haloC₁-C₆alkyl;

R^(a) is independently H, C(O)NR^(c) ₂, OR^(c), NH₂, halo, C₁-C₆alkyl,or C₂-C₆alkenyl, said alkyl or alkenyl is optionally substituted withOH, C₁-C₄alkoxy, NH₂, halo, haloC₁-C₄alkyl, C₃-C₆cycloalkyl, orC₂-C₄alkenyl;R^(c) is independently H or C₁-C₄alkyl optionally substituted withC₂-C₃alkenyl, C₃-C₆cycloalkyl, C₁-C₃alkoxy, OH, halo, NH₂,C₁-C₃alkylamino, or C₁-C₃dialkylamino;T is independently C₂-C₃alkenyl, —C(O)—, —(CR^(a) ₂)_(q)—, —C(═CH₂)—,—(CR^(a) ₂)_(q)—C(═CH₂)—, —C(═CH₂)—(CR^(a) ₂)_(q)—, —C(═NH)—, —(CR^(a)₂)_(q)—C(═NH)—, or —C(═NH₂)—(CR^(a) ₂)_(q)—;Y is a bond, —C(O)NR^(c)—, —NR^(c)C(O)—, or —NR^(c)—;U is H, COOR¹¹, OH, heteroaryl or heterocyclic;n is independently 0, 1, 2 or 3;m is independently 0, 1 or 2;q is independently 0, 1, 2, or 3;s is independently 0, 1 or 2;t is independently 0, 1, or 2;v is independently 1, 2, 3 or 4;z is independently 0, 1, 2, 3 or 4;or a pharmaceutically acceptable salt thereof.In a first embodiment,R¹ is selected from the group consisting of C₁-C₆alkyl, —(CR^(a)₂)_(n)COOR¹¹, -T-NHR⁵, —(CR^(a) ₂)_(n)NR⁶SO₂R⁶, —(CR^(a) ₂)_(n)SO₂NR⁶R⁶,—(CR^(a) ₂)_(n)C(O)NR^(c)SO₂N(R^(c))₂, —(CR^(a) ₂)_(n)C(O)R⁶, —(CR^(a)₂)_(n)CONR⁶R⁶, —(CR^(a) ₂)_(n)CONR⁶OR⁶, —(CR^(a) ₂)_(n)NR⁶C(O)R⁶,—(CR^(a) ₂)_(n)OR⁶, —(CR^(a) ₂)_(n)S(O)R^(c), —(CR^(a) ₂)_(n)S(O)₂R^(c),and nitrogen containing 5-membered heterocyclic, heteroaryl orheterocyclenyl ring, wherein the alkyl and 5-membered ring can beoptionally substituted with OR^(c), SR^(c), NH₂, nitro, CN, amide,COOR¹¹, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, C₁-C₆hydroxyalkyl,C₂-C₆alkenyl, C₁-C₆alkyl-C(═O)O—, C₁-C₆alkyl-C(═O)—, C₂-C₆alkynyl, halogroup, hydroxyalkoxy, —SO₂NR^(c)R^(c), —NR^(c)SO₂R^(c),C₁-C₆alkylsulfonyl, C₁-C₆alkylamino or di(C₁-C₆)alkylamino;R² is selected from the group consisting of aryl, heteroaryl,—W—(CR^(a)R⁹)_(t)R⁷, and heterocyclic, wherein W is NR^(C) or O, whereinthe aryl, heteroaryl, or heterocyclic is optionally substituted with R¹²selected from the group consisting of halo, CN, haloC₁-C₆alkyl,C₁-C₆alkyl, —(CR^(a) ₂)_(z)OR^(c), —(CR^(a) ₂)_(z)NHR⁸, —(CR^(a)₂)_(z)C(O)NR^(c)R^(c), —(CR^(a) ₂)_(z)COOR¹⁰, —(CR^(a) ₂)_(z)aryl,—(CR^(a) ₂)_(z)heteroaryl, —(CR^(a) ₂)_(z)heterocyclic, —(CR^(a)₂)_(z)C₃-C₈cycloalkyl, —(CR^(a) ₂)_(z)cyclenyl, and —(CR^(a)₂)_(z)heterocyclenyl, wherein the alkyl, aryl, heteroaryl, heterocyclic,cycloalkyl, cyclenyl and heterocyclenyl of R¹² can be optionallysubstituted with OH, NH₂, nitro, CN, CON(R^(c))₂, —(CR^(a) ₂)_(z)COOR¹⁰,C₁-C₆alkoxy, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆haloalkoxy,C₁-C₆hydroxyalkyl, C₂-C₆alkenyl, C₁-C₆alkyl-C(═O)O—, C₁-C₆alkyl-C(═O)—,C₂-C₆alkynyl, halo group, hydroxyalkoxy, —SO₂NR^(c)R^(c),—NR^(c)SO₂R^(c), C₁-C₆alkylsulfonyl, C₁-C₆alkylamino ordi(C₁-C₆)alkylamino;R³ is selected from the group consisting of H, —(CR^(a) ₂)_(q)NR^(c)R⁸,—(CR^(a) ₂)_(q)OR⁸, —(CR^(a) ₂)_(q)SR⁸, —(CR^(a) ₂)_(q)C(O)R⁸, —(CR^(a)₂)_(q)S(O)R⁸, —(CR^(a) ₂)_(q)S(O)₂R⁸, —(CR^(a) ₂)_(q)CONR^(c)R⁸,—(CR^(a) ₂)_(q)NR^(c)C(O)R⁸, -T-C₁-C₆alkyl, C₂-C₆alkenyl, -T-aryl,-T-heteroaryl, -T-heterocyclic, -T-C₃-C₇cycloalkyl, -T-cyclenyl, and-T-heterocyclenyl,wherein the alkyl, alkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl,cyclenyl and heterocyclenyl can be optionally substituted with halo, SH,OR^(c), haloC₁-C₆alkyl, haloC₁-C₆alkoxy, —(CR^(a) ₂)_(z)CN, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, —(CR^(a) ₂)_(z)C(O)OR¹¹, —(CR^(a)₂)_(z)C(O)R⁸, —(CR^(a) ₂)_(z)OR⁸, —(CR^(a) ₂)_(z)NR^(c)R⁸, —(CR^(a)₂)_(z)S(O)₂R⁸, —(CR^(a) ₂)_(z)C(O)NR^(c)R⁸, —(CR^(a) ₂)_(z)aryl,—(CR^(a) ₂)_(z)heteroaryl, —(CR^(a) ₂)_(z) C₃-C₈cycloalkyl, —(CR^(a)₂)_(z)heterocyclic, —(CR^(a) ₂)_(z)heterocyclenyl, —(CR^(a)₂)_(z)cyclenyl, —(CR^(a) ₂)_(z)SO₂NR^(c)R⁸, or —(CR^(a) ₂)_(z)O(CR^(a)₂)_(z)Y(CR^(a) ₂)_(v)U,said alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl,heterocyclic, heterocyclenyl and cyclenyl can further be substitutedwith SH, OH, NH₂, nitro, CN, CON(R^(c))₂, COOR¹⁰, C₁-C₆alkoxy,C₁-C₆alkyl, C₁-C₆alkoxyC₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl,C₁-C₆haloalkoxy, C₁-C₆hydroxyalkyl, C₁-C₆alkyl-C(═O)O—,C₁-C₆alkyl-C(═O)—, C₂-C₆alkynyl, halo group, hydroxyalkoxy,—SO₂NR^(c)R^(c), —NR^(c)SO₂R^(c), C₁-C₆alkylsulfonyl, C₁-C₆alkylamino ordi(C₁-C₆)alkylamino;R⁴ is selected from the group consisting of C₁-C₆alkyl, —(CR^(a)₂)_(m)aryl, —(CR^(a) ₂)_(m)heteroaryl, —(CR^(a) ₂)_(m)heterocyclic,—(CR^(a) ₂)_(m)C₃-C₈cycloalkyl, —(CR^(a) ₂)_(m)cyclenyl, and —(CR^(a)₂)_(m)heterocyclenyl, wherein the alkyl, aryl, heteroaryl, heterocyclic,cycloalkyl, cyclenyl, and heterocyclenyl can be optionally substitutedwith OH, SH, NH₂, nitro, CN, CON(R^(c))₂, COOR¹¹, C₁-C₆alkoxy,C₁-C₆alkyl, C₃-C₆cycloalkyl, haloC₂-C₆alkenyl, C₂-C₆alkenyl,C₂-C₆alkenoxy, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, C₁-C₆hydroxyalkyl,C₁-C₆alkyl-C(═O)O—, C₁-C₆alkyl-C(═O)—, C₂-C₆alkynyl, halo group,hydroxyalkoxy, —SO₂NR^(c)R^(c), —NR^(c)SO₂R^(c), C₁-C₆alkylsulfonyl,C₁-C₆alkylamino or di(C₁-C₆)alkylamino;R⁵ is independently selected from the group consisting of H, C₁-C₆alkyl,—C₀-C₆alkyl-C₃-C₈cycloalkyl, —C₀-C₆alkyl-heteroaryl, —C₀-C₆alkyl-aryl,and —C₀-C₆alkylheterocyclic, wherein the alkyl, cycloalkyl, heteroaryl,aryl, and heterocyclic can be optionally substituted with C₂-C₃alkenyl,C₃-C₆cycloalkyl, C₁-C₃alkoxy, OH, halo, NH₂, C₁-C₃alkylamino,C₁-C₃dialkylamino or COOR¹¹;R⁶ is independently selected from the group consisting of H, C₁-C₆alkyl,—C₀-C₆alkyl-C₃-C₈cycloalkyl, —C₀-C₆alkyl-heteroaryl, —C₀-C₆alkyl-aryl,and —C₀-C₆alkylheterocyclic, wherein the alkyl, cycloalkyl, heteroaryl,aryl, and heterocyclic can be optionally substituted with C₂-C₃alkenyl,C₃-C₆cycloalkyl, C₁-C₃alkoxy, OH, halo, NH₂, C₁-C₃alkylamino,C₁-C₃dialkylamino or COOR¹¹;R⁷ is selected from the group consisting of H, C₁-C₆alkyl, C₂-C₆alkenyl,C₃-C₈cycloalkyl, aryl, heteroaryl, heterocyclic, wherein the alkyl,alkenyl, cycloalkyl, aryl, heteroaryl or heterocyclic can be optionallysubstituted with halo, nitro, CN, C₁-C₆haloalkyl, C₁-C₆haloalkoxy,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkyl, —C₀-C₆alkyl-C₃-C₈cycloalkyl,—C₀-C₆alkyl-heteroaryl, —C₀-C₆alkyl-aryl, —C₀-C₆alkylheterocyclic,—C₀-C₆alkylheterocyclenyl, —C₀-C₆alkylcyclenyl, —(CR^(a) ₂)_(z)NHR⁵,—(CR^(a) ₂)_(z)NR⁵SO₂R⁶, —(CR^(a) ₂)_(z)SO₂NR⁵R⁶, —(CR^(a) ₂)_(z)C(O)R⁵,—(CR^(a) ₂)_(z)C(O)OR¹⁰, —(CR^(a) ₂)_(z)CONR⁵R⁶, —(CR^(a)₂)_(z)CONR⁵OR⁶, —(CR^(a) ₂)_(z)NR⁵C(O)R⁶, —(CR^(a) ₂)_(z)OR⁵, —(CR^(a)₂)_(z)S(O)R^(c), and —(CR^(a) ₂)_(z)S(O)₂R^(c);R⁸ is independently selected from the group consisting of H, —(CR^(a)₂)_(s)-heteroaryl, —(CR^(a) ₂)_(s)-aryl, —(CR^(a) ₂)_(s)-heterocyclic,—(CR^(a) ₂)_(s)-heterocyclenyl, —(CR^(a) ₂)_(s)-cyclenyl, —(CR^(a)₂)_(s)C₃-C₇cycloalkyl, and C₁-C₆alkyl, wherein the heteroaryl, aryl,heterocyclic, heterocyclenyl, cyclenyl, cycloalkyl, and alkyl can beoptionally substituted with OH, NH₂, nitro, CN, CON(R^(c))₂, COOR¹¹,C₁-C₆alkoxy, C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl, C₁-C₆haloalkoxy,C₁-C₆hydroxyalkyl, C₁-C₆alkyl-C(═O)O—, C₁-C₆alkyl-C(═O)—, C₂-C₆alkynyl,halo group, hydroxyalkoxy, —SO₂NR^(c)R^(c), —NR^(c)SO₂R^(c),C₁-C₆alkylsulfonyl, C₁-C₆alkylamino or di(C₁-C₆)alkylamino;R⁹ is independently selected from the group consisting of H, C₁-C₆alkyl,C₁-C₆haloalkyl, C₃-C₈cycloalkyl, aryl, heteroaryl, and heterocyclic,wherein the alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic can beoptionally substituted with —C₀-C₆alkylOR^(c), C₀-C₆alkylN(R^(c))₂,COOR¹⁹, nitro, CN, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆haloalkoxy,C₁-C₆hydroxyalkyl, C₂-C₆alkenyl, C₁-C₆alkyl-C(═O)O—, C₁-C₆alkyl-C(═O)—,C₂-C₆alkynyl, halo group, hydroxyalkoxy, —SO₂NR^(c)R^(c),—NR^(c)SO₂R^(c), C₁-C₆alkylsulfonyl, heterocyclic, or C(O)NHR^(c);

-   -   R¹⁰ is independently selected from the group consisting of        C₁-C₆alkyl, —(CR^(c) ₂)_(n)C₃-C₈cycloalkyl, —(CR^(c)        ₂)_(z)-heteroaryl, —(CR^(c) ₂)_(z)-aryl, and —(CR^(c)        ₂)_(z)-heterocyclic, wherein the heteroaryl, aryl, heterocyclic,        cycloalkyl and alkyl can be optionally substituted with        C₁-C₆alkyl, OH, halo, or haloC₁-C₆alkyl;

R¹¹ is independently selected from the group consisting of H,C₁-C₆alkyl, —(CR^(c) ₂)_(z)C₃-C₈cycloalkyl, —(CR^(c) ₂)_(z)heteroaryl,—(CR^(c) ₂)_(z)aryl, and —(CR^(c) ₂)_(z)heterocyclic wherein theheteroaryl, aryl, heterocyclic, cycloalkyl and alkyl can be optionallysubstituted with C₁-C₆alkyl, OH, halo, or haloC₁-C₆alkyl;

R¹⁷ is independently selected from the group consisting of H, halo,C₁-C₆alkyl, —(CR^(c) ₂)_(z)C₃-C₈cycloalkyl, —(CR^(c) ₂)_(z)heteroaryl,—(CR^(c) ₂)_(z)aryl, and —(CR^(c) ₂)_(z)heterocyclic wherein theheteroaryl, aryl, heterocyclic, cycloalkyl and alkyl can be optionallysubstituted with C₁-C₆alkyl, OH, halo, or haloC₁-C₆alkyl;R^(a) is independently H, OR^(c), NH₂, halo, C₁-C₆alkyl, orC₂-C₆alkenyl, said alkyl or alkenyl is optionally substituted with OH,C₁-C₄alkoxy, NH₂, halo, haloC₁-C₄alkyl, C₃-C₆cycloalkyl, orC₂-C₄alkenyl;R^(c) is independently H or C₁-C₃alkyl optionally substituted withC₂-C₃alkenyl, C₃-C₆cycloalkyl, C₁-C₃alkoxy, OH, halo, NH₂,C₁-C₃alkylamino, or C₁-C₃dialkylamino;T is independently C₂-C₃alkenyl, —(CR^(a) ₂)_(q)—, —C(═CH₂)—, —(CR^(a)₂)_(q)—C(═CH₂)—, —C(═CH₂)—(CR^(a) ₂)_(q)—, —C(═NH)—, —(CR^(a)₂)_(q)—C(═NH)—, or —C(═NH)—(CR^(a) ₂)_(q)—;Y is a bond, —C(O)NR^(c)—, —NR^(c)C(O)—, or —NR^(c)—;U is H, COOR¹¹, OH, heteroaryl or heterocyclic;n is independently 0, 1, 2 or 3;m is independently 0, 1 or 2;q is independently 0, 1, 2, or 3;s is independently 0, 1 or 2;t is independently 0, 1, or 2;v is independently 1, 2, 3 or 4;z is independently 0, 1, 2 or 3;In one embodiment, R¹⁰ is independently C₁-C₆alkyl optionallysubstituted with OH, halo, or haloC₁-C₆alkyl.In a second embodiment,R¹ is selected from the group consisting of COOR¹¹, —NHR^(c),—NR^(c)SO₂R^(c), —SO₂NR^(c)R^(c), —C(O)R^(c), —CONR^(c)R^(c),—CONR^(c)OR^(c), —OR^(c), and nitrogen containing 5-memberedheterocyclenyl or heteroaryl ring, wherein the 5-membered ring can beoptionally substituted with OR^(c), SR^(c), NH₂, nitro, CN, amide,COOR¹¹, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, C₁-C₆hydroxyalkyl,C₂-C₆alkenyl, C₁-C₆alkyl-C(═O)O—, C₁-C₆alkyl-C(═O)—, C₂-C₆alkynyl, halogroup, hydroxyalkoxy, —SO₂NR^(c)R^(c), —NR^(c)SO₂R^(c),C₁-C₆alkylsulfonyl, C₁-C₆alkylamino or di(C₁-C₆)alkylamino;R² is selected from the group consisting of aryl, heteroaryl,W—CR^(a)R⁹)R⁷, and heterocyclic, wherein W is NR^(C) or O, wherein thearyl, heteroaryl, and heterocyclic is optionally substituted with R¹²selected from the group consisting of halo, CN, haloC₁-C₆alkyl,C₁-C₆alkyl, —(CR^(a) ₂)OR^(c), and —(CR^(a) ₂)C(O)NR^(c)R^(c), whereinthe alkyl of R¹² can be optionally substituted with OH, CN, halo,haloC₁-C₆alkyl, or CON(R^(c))₂;R³ is selected from the group consisting of —NR^(c)R⁸, —OR⁸, —SR⁸,—C(O)R⁸, —S(O)R⁸, —S(O)₂R⁸, —CONR^(c)R⁸, —NR^(c)C(O)R⁸, -T-C₁-C₆alkyl,C₂-C₆alkenyl, -T-aryl, -T-heteroaryl, -T-heterocyclic,-T-C₃-C₇cycloalkyl, -T-cyclenyl, and -T-heterocyclenyl, wherein thealkyl, alkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl, cyclenyl andheterocyclenyl can be optionally substituted with halo, OR^(c),haloC₁-C₆alkyl, haloC₁-C₆alkoxy, —(CR^(a) ₂)_(z)CN, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, —(CR^(a) ₂)_(z)C(O)OR¹¹, —(CR^(a)₂)_(z)C(O)R⁸, —(CR^(a) ₂)_(z)OR⁸, —(CR^(a) ₂)_(z)NR^(c)R⁸, —(CR^(a)₂)_(z)S(O)₂R⁸, —(CR^(a) ₂)_(z)C(O)NR^(c)R⁸, —(CR^(a) ₂)_(z)aryl,—(CR^(a)kheteroaryl, —(CR^(a) ₂)_(z)C₃-C₈cycloalkyl, —(CR^(a)₂)_(z)heterocyclic, —(CR^(a) ₂)_(z)SO₂NR^(c)R⁸, or —(CR^(a)₂)_(z)O(CR^(a) ₂)_(z)Y(CR^(a) ₂)_(z)U,said alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, andheterocyclic can further be substituted with OH, halo, or C₂-C₆alkenyl;R⁴ is selected from the group consisting of —(CR^(a) ₂)aryl, —(CR^(a)₂)heteroaryl, —(CR^(a) ₂)heterocyclic, —(CR^(a) ₂)C₃-C₈cycloalkyl,—(CR^(a) ₂)cyclenyl, and —(CR^(a) ₂)heterocyclenyl, wherein the aryl,heteroaryl, heterocyclic, cycloalkyl, cyclenyl, and heterocyclenyl canbe optionally substituted with OH, SH, NH₂, nitro, CN, CON(R^(c))₂,COOR¹¹, C₁-C₆alkoxy, C₁-C₆alkyl, C₃-C₆cycloalkyl, haloC₂-C₆alkenyl,C₂-C₆alkenyl, C₂-C₆alkenoxy, C₁-C₆haloalkyl, C₁-C₆haloalkoxy,C₁-C₆hydroxyalkyl, C₁-C₆alkyl-C(═O)O—, C₁-C₆alkyl-C(═O)—, C₂-C₆alkynyl,halo group, hydroxyalkoxy, —SO₂NR^(c)R^(c), —NR^(c)SO₂R^(c),C₁-C₆alkylsulfonyl, C₁-C₆alkylamino or di(C₁-C₆)alkylamino;R⁷ is selected from the group consisting of C₁-C₆alkyl, C₃-C₈cycloalkyl,heteroaryl, aryl, and heterocyclic, wherein the alkyl, cycloalkyl,heteroaryl, aryl or heterocyclic can be optionally substituted withhalo, nitro, CN, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, C₁-C₆alkyl, or—(CR^(a) ₂)_(z)OR^(c);R⁸ is independently selected from the group consisting of —(CR^(a)₂)-heteroaryl, —(CR^(a) ₂)-aryl, —(CR^(a) ₂)-heterocyclic, —(CR^(a)₂)-heterocyclenyl, —(CR^(a) ₂)cyclenyl, —(CR^(a) ₂)cycloalkyl, andC₁-C₆alkyl, wherein the heteroaryl, aryl, heterocyclic, heterocyclenyl,cyclenyl, cycloalkyl, and alkyl can be optionally substituted with OH,C₁-C₆alkoxy, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆haloalkoxy,C₁-C₆hydroxyalkyl, or halo group;R⁹ is H, C₁-C₃alkyl, C₁-C₃haloalkyl, C₃-C₄cycloalkyl, wherein the alkylor cycloalkyl can be optionally substituted with OR^(c), N(R^(c))₂,heterocyclic, C(O)NHCH₂CH₂OH, C(O)NH₂, or C(O)NHC₁-C₃alkyl;R¹¹ is independently selected from the group consisting of H andC₁-C₆alkyl, wherein alkyl can be optionally substituted with OH or halo;R¹⁷ is independently selected from the group consisting of H or halo;R^(a) is independently H, OR^(c), NH₂, halo, C₁-C₆alkyl, orC₂-C₆alkenyl, said alkyl or alkenyl is optionally substituted with OH,C₁-C₄alkoxy, NH₂, F, CF₃, C₃-C₆cycloalkyl, or C₂-C₄alkenyl;R^(c) is independently H or C₁-C₃alkyl optionally substituted withC₂-C₃alkenyl, C₃-C₆cycloalkyl, C₁-C₃alkoxy, OH, halo, NH₂,C₁-C₃alkylamino, or C₁-C₃dialkylamino;T is independently —(CR^(a) ₂)_(q)—, or —C(═CH₂)—;Y is a bond, —C(O)NR^(c)—, —NR^(c)C(O)—, or —NR^(c)—;U is H, COOR¹¹, OH, heteroaryl or heterocyclic;q is independently 0 or 1;v is independently 1 or 2; andz is independently 0, 1 or 2.In a third embodiment,R¹ is selected from the group consisting of COOR¹¹, —NHR^(c),—NR^(c)SO₂R^(c), —SO₂NR^(c)R^(c), —C(O)R^(c), —CONR^(c)R^(c),—CONR^(c)OR^(c), —OR^(c), and nitrogen containing 5-memberedheterocyclenyl ring, wherein the 5-membered ring can be optionallysubstituted with OR^(c), SR^(c), NH₂, nitro, CN, amide, COOR¹¹,C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, C₁-C₆hydroxyalkyl,C₂-C₆alkenyl, C₁-C₆alkyl-C(═O)O—, C₁-C₆alkyl-C(═O)—, C₂-C₆alkynyl, halogroup, hydroxyalkoxy, —SO₂NR^(c)R^(c), —NR^(c)SO₂R^(c),C₁-C₆alkylsulfonyl, C₁-C₆alkylamino or di(C₁-C₆)alkylamino;R² is selected from the group consisting of aryl, heteroaryl, and—NR^(c)—(CR^(a)R⁹)R⁷, wherein the aryl, or heteroaryl is optionallysubstituted with R¹² selected from the group consisting of halo, CN,haloC₁-C₆alkyl, C₁-C₆alkyl, —(CR^(a) ₂)OR^(c), wherein the alkyl of R¹²can be optionally substituted with OH, CN, halo, haloC₁-C₆alkyl, orCON(R^(c))₂;R³ is selected from the group consisting of -T-aryl, -T-heteroaryl, and-T-heterocyclic, wherein the heteroaryl, and heterocyclic can beoptionally substituted with halo, OR^(c), haloC₁-C₆alkyl,haloC₁-C₆alkoxy, —(CR^(a) ₂)_(z)CN, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, —(CR^(a) ₂)_(z)C(O)OR¹¹, —(CR^(a) ₂)_(z)C(O)R⁸, —(CR^(a)₂)_(z)OR⁸, -(CR^(a) ₂)_(z)NR^(c)R⁸, —(CR^(a) ₂)_(z)S(O)₂R⁸, —(CR^(a)₂)_(z)C(O)NR^(c)R⁸, —(CR^(a) ₂),aryl, —(CR^(a) ₂)_(z)heteroaryl,—(CR^(a) ₂)_(z)C₃-C₈cycloalkyl, —(CR^(a) ₂)_(z)heterocyclic, —(CR^(a)₂)_(z)SO₂NR^(c)R⁸, or —(CR^(a) ₂)_(z)O(CR^(a) ₂)_(z)Y(CR^(a) ₂)_(z)U;said alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, andheterocyclic can further be substituted with OH, halo, or C₂-C₆alkenyl;R⁴ is selected from the group consisting of —(CR^(a) ₂)aryl, —(CR^(a)₂)C₃-C₆cycloalkyl, and —(CR^(a) ₂)C₃-C₆cyclenyl, wherein the aryl,cycloalkyl, and cyclenyl can be optionally substituted with OH, SH, NH₂,nitro, CN, CON(R^(c))₂, COOR¹¹, C₁-C₆alkoxy, C₁-C₆alkyl,C₃-C₆cycloalkyl, haloC₂-C₆alkenyl, C₂-C₆alkenyl, C₂-C₆alkenoxy,C₂-C₆haloalkyl, C₁-C₆haloalkoxy, C₁-C₆hydroxyalkyl, C₁-C₆alkyl-C(═O)O—,C₁-C₆alkyl-C(═O)—, C₂-C₆alkynyl, halo group, hydroxyalkoxy,—SO₂NR^(c)R^(c), —NR^(c)SO₂R^(c), C₁-C₆alkylsulfonyl, C₁-C₆alkylamino ordi(C₁-C₆)alkylamino;R⁷ is C₃-C₆cycloalkyl optionally substituted with halo, nitro, CN,C₁-C₆haloalkyl, C₁-C₆haloalkoxy, C₁-C₆alkyl, or —(CR^(a) ₂)_(z)OR^(c);R⁹ is C₁-C₃alkyl;

R¹⁷ is H;

and all other substituents are defined in the first embodiment underFormula I.In a fourth embodiment,R¹ is COOH or a nitrogen containing 5-membered heteroaryl, heterocyclylor heterocyclenyl ring selected from the group consisting of tetrazolyl,oxadiazolyl, oxadiazolone, dihydro-oxadiazolyl, triazolyl,dihydro-triazolyl, dihydro-triazolone, pyrrolidinyl, and imidazolyl,wherein the nitrogen containing 5-membered ring can be optionallysubstituted with halo, C₁-C₆alkyl, haloC₁-C₆alkyl, NH₂, OR^(c), SR^(c),COOH, or —NR^(c)SO₂R^(c).and all other substituents are as defined in the first embodiment.In a fifth embodiment of the foregoing embodiments, R¹ is COOH or anitrogen containing 5-membered heteroaryl, heterocyclyl orheterocyclenyl ring selected from the group consisting of tetrazolyl,oxadiazolyl, oxadiazolone, dihydro-oxadiazolyl, triazolyl,dihydro-triazolyl, dihydro-triazolone, pyrrolidinyl, and imidazolyl,wherein the nitrogen containing 5-membered ring can be optionallysubstituted with halo, C₁-C₆alkyl, haloC₁-C₆alkyl, NH₂, OR^(c), SR^(c),COOH, or —NR^(c)SO₂R^(c).In a sixth embodiment of the foregoing embodiments,

R¹ is COOH,

wherein R^(d) is CH₃ or H.In one embodiment, R¹ is

wherein R^(d) is CH₃ or H.

In another embodiment, R¹ is COOH,

Or

In another embodiment, R¹ is COOH,

In a further embodiment, R¹ is

In yet a further embodiment, R¹ is

In another aspect of the invention for the foregoing embodiments, R⁷ iscyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In anotherembodiment, R⁷ is cyclobutyl.

In another aspect of the invention for the foregoing embodiments, R² is

R^(e) is H, —(CR^(a) ₂)_(z)C(O)OR¹⁰, halo, haloC₁-C₃alkyl or C₁-C₃alkyl;K and L are independently CR¹⁴ or N;

R¹⁴ is independently H, halo, CN, haloC₁-C₆alkyl, C₁-C₆alkyl, —(CR^(a)₂)_(z)C(O)NR^(c)R^(c), —(CR^(a) ₂)_(z)OR^(c), —(CR^(a) ₂)_(z)aryl,—(CR^(a) ₂)_(z)heteroaryl, —(CR^(a) ₂)_(z)heterocyclic, —(CR^(a)₂)_(z)C₃-C₈cycloalkyl, —(CR^(a) ₂)_(z)cyclenyl, —(CR^(a)₂)_(z)heterocyclenyl, wherein the alkyl, aryl, heteroaryl, heterocyclic,cycloalkyl, cyclenyl or heterocyclenyl can be optionally substitutedwith OH, CN, halo, haloC₁-C₃alkyl, or CON(R^(c))₂; and

h is 0 or 1.In one embodiment, R² is

and R_(j) is H or methyl, R^(h) is halo, NR^(c)R^(c), hydroxyC₁-C₄alkyl,hydroxyC₁-C₄alkoxy, —OC₁-C₃alkylOC₁-C₃alkyl, C₁-C₄alkyl or C₁-C₄alkoxy;a is 0, 1 or 2.In one embodiment, R² is

and R_(j) is H or methyl. In another embodiment, R² is

In a further embodiment, R² is

In yet a further embodiment, R² is

and R^(e) is halo.

In another aspect of the invention for the foregoing embodiments, R³ is-T-heterocyclic optionally substituted with halo, OR^(c),haloC₁-C₆alkyl, haloC₁-C₆alkoxy, CN, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, —(CR^(a) ₂)_(z)C(O)OR¹¹, —(CR^(a) ₂)_(z)C(O)R⁵, —(CR^(a)₂)_(z)OR⁵, —(CR^(a) ₂)_(z)NR^(c)R⁵, —(CR^(a) ₂)_(z)S(O)₂R⁵, —(CR^(a)₂)_(z)C(O)NR^(c)R⁵, —(CR^(a) ₂)_(z)aryl, —(CR^(a) ₂)_(z)heteroaryl,—(CR^(a) ₂)_(n)C₃-C₈cycloalkyl, —(CR^(a) ₂)_(z)heterocyclic, —(CR^(a)₂)_(z)SO₂NR^(c)R⁵, or —(CR^(a) ₂)_(z)O(CR^(a) ₂)_(z)Y(CR^(a) ₂)_(v)U;

said alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, andheterocyclic can further be substituted with OH, halo, or C₂-C₆alkenyl.In one embodiment, the heteroaryl or heterocyclic group of R³ ispyridyl, morpholinyl, thiomorpholinyl, phenyl, piperidinyl,benzothiophenyl, thiazolyl, pyrimidinyl, oxazolyl, imidazolyl,pyrazolyl, piperizinyl, tetrahydrofuranyl, benzofuranyl, quinoxalinyl,pyrazolyl, naphthalenyl, dihydro-indenyl, quinolinyl, isoindolyl,isoquinolinyl, isoxazolyl, furanyl, oxadiazolyl, octahydroquinolinyl,octahydroisoquinolinyl, azetidinyl, oxazepanyl, or oxazolidinyl.

In yet another aspect of the invention for the foregoing embodiments, R³is

X is NR¹⁹, CR¹⁶ ₂, S, or O;

R¹⁵ is independently selected from the group consisting of phenyl, 5 or6-membered heterocyclic or heteroaryl, haloC₁-C₆alkyl, haloC₂-C₆alkenyl,halo, haloC₁-C₆alkoxy, C₁-C₆alkoxy, C₁-C₆alkoxyC₁-C₆alkyl, C₁-C₆alkyl,C₂-C₆alkenyl, C₃-C₆cycloalkyl, amino, CN, OH, and SH; two adjacent R¹⁵form a fused C₃-C₇cycloalkyl or heterocyclic ring; two non-adjacent R¹⁵form a C₁-C₃alkylene; or two R¹⁵ attached to the same carbon form aC₃-C₇cycloalkyl or heterocyclic ring, wherein the phenyl, heteroaryl,cycloalkyl or heterocyclic can be optionally substituted with R¹³selected from the group consisting of haloC₁-C₆alkyl, haloC₂-C₆alkenyl,halo, haloC₁-C₆alkoxy, C₁-C₆alkoxy, C₁-C₆alkoxyC₁-C₆alkyl, C₁-C₆alkyl,C₂-C₆alkenyl, amino, CN, OH, or SH;R¹⁶ is independently selected from the group consisting of H,haloC₁-C₆alkyl, haloC₂-C₆alkenyl, halo, haloC₁-C₆alkoxy, C₁-C₆alkoxy,C₁-C₆alkoxyC₁-C₆alkyl, C₁-C₆alkyl, C₂-C₆alkenyl, amino, CN, OH, and SH;R¹⁹ is independently selected from the group consisting of H,haloC₁-C₆alkyl, haloC₂-C₆alkenyl, C₁-C₆alkoxyC₁-C₆alkyl, C₁-C₆alkyl,C₂-C₆alkenyl;f is 0, 1 or 2;g is 0, 1 or 2;j is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8.In one embodiment, R¹⁵ is independently selected from the groupconsisting of phenyl, 5 or 6-membered heterocyclic or heteroaryl,haloC₁-C₆alkyl, haloC₂-C₆alkenyl, halo, haloC₁-C₆alkoxy, C₁-C₆alkoxy,C₁-C₆alkoxyC₁-C₆alkyl, C₁-C₆alkyl, C₂-C₆alkenyl, C₃-C₆cycloalkyl, amino,CN, OH, and SH; two adjacent R¹⁵ form a fused C₃-C₇cycloalkyl orheterocyclic ring; or two R¹⁵ attached to the same carbon form aC₃-C₇cycloalkyl or heterocyclic ring, wherein the phenyl, heteroaryl,cycloalkyl or heterocyclic can be optionally substituted with R¹³selected from the group consisting of haloC₁-C₆alkyl, haloC₂-C₆alkenyl,halo, haloC₁-C₆alkoxy, C₁-C₆alkoxy, C₁-C₆alkoxyC₁-C₆alkyl, C₁-C₆alkyl,C₂-C₆alkenyl, amino, CN, OH, or SH; R¹⁶ is independently selected fromthe group consisting of H, haloC₁-C₆alkyl, haloC₂-C₆alkenyl, halo,haloC₁-C₆alkoxy, C₁-C₆alkoxy, C₁-C₆alkoxyC₁-C₆alkyl, C_(r) C₆alkyl,C₂-C₆alkenyl, amino, CN, OH, and SH.In another embodiment, R¹⁵ is independently halo, C₁-C₃alkyl,C₁-C₃haloalkyl, C₁-C₃alkoxy, C₁-C₃alkoxyC₁-C₃alkyl, or NH₂In one embodiment, j is independently 0, 1 or 2.In one embodiment, f is 0 or 1.In one embodiment, R³ is

In a yet another aspect of the invention for the foregoing embodiments,R³ is

X is CR¹⁶ ₂, S, or O;

R¹³, R¹⁵ and R¹⁶ are independently H, haloC₁-C₆alkyl, haloC₂-C₆alkenyl,halo, haloC₁-C₆alkoxy, C₁-C₆alkoxy, C₁-C₆alkoxyC₁-C₆alkyl, C₁-C₆alkyl,C₃-C₆cycloalkyl, C₂-C₆alkenyl, amino, CN, OH, or SH;A is phenyl, or 5-6 membered heteroaryl;r is independently 0, 1, 2, 3, 4, or 5; andj is independently 0, 1, 2, or 3.In one embodiment, R¹³, R¹⁵ and R¹⁶ are independently H, halo,C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy or NH₂.In one embodiment, r is independently 0 or 1; j is independently 0 or 1.In another embodiment, X is O.In a further embodiment, A is phenyl, pyridyl or oxadiazolyl.In another embodiment, R³ is

In a further embodiment, R³ is

In another aspect of the invention for the foregoing embodiments, R³ is

Ring B is a fused C₃-C₇cycloalkyl;

X is CR¹⁶ ₂, S, or O;

R¹³, R¹⁵ and R¹⁶ are independently H, haloC₁-C₆alkyl, haloC₂-C₆alkenyl,halo, haloC₁-C₆alkoxy, C₁-C₆alkoxy, C₁-C₆alkoxyC₁-C₆alkyl, C₁-C₆alkyl,C₃-C₆cycloalkyl, C₂-C₆alkenyl, amino, CN, OH, or SH;r is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; andj is independently 0, 1, 2, 3, or 4.In one embodiment, R¹³, R¹⁵ and R¹⁶ are independently H, halo,C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy or NH₂.In one embodiment, r is independently 0 or 1; j is independently 0 or 1.In another embodiment, X is O.

In a further aspect of the invention for the foregoing embodiments, R³is

R¹⁵ is independently haloC₁-C₆alkyl, haloC₂-C₆alkenyl, halo,haloC₁-C₆alkoxy, C₁-C₆alkoxy, C₁-C₆alkoxyC₁-C₆alkyl, C₁-C₆alkyl,C₂-C₆alkenyl, C₃-C₆cycloalkyl, amino, CN, OH, or SH; f is 0, 1 or 2; jis independently 0, 1, 2, 3, 4, 5, or 6.In one embodiment, R¹⁵ is independently halo, C₁-C₃alkyl,C₁-C₃haloalkyl, C₁-C₃alkoxy, C₁-C₃alkoxyC₁-C₃alkyl, or NH₂In one embodiment, j is independently 0, 1 or 2.In one embodiment, f is 0 or 1.

In a further aspect of the invention for the foregoing embodiments, R³is

X is CH₂ or 0;

R¹⁸ and R²⁰ are independently H, haloC₁-C₆alkyl, haloC₂-C₆alkenyl, halo,haloC₁-C₆alkoxy, C₁-C₆alkoxy, C₁-C₆alkoxyC₁-C₆alkyl, C₁-C₆alkyl,C₃-C₆cycloalkyl, C₂-C₆alkenyl, amino, CN, OH, or SH; andf is 0, 1 or 2.

In yet a further aspect of the invention for the foregoing embodiments,R³ is

R¹⁵ is independently haloC₁-C₆alkyl, haloC₂-C₆alkenyl, halo,haloC₁-C₆alkoxy, C₁-C₆alkoxy, C₁-C₆alkoxyC₁-C₆alkyl, C₁-C₆alkyl,C₃-C₆cycloalkyl, C₂-C₆alkenyl, amino, CN, OH, or SH;j is independently 0, 1, 2, 3, or 4.In one embodiment, R¹⁵ is independently halo, C₁-C₃alkyl,C₁-C₃haloalkyl, C₁-C₃alkoxy, C₁-C₃alkoxyC₁-C₃alkyl, or NH₂In one embodiment, j is independently 0 or 1.

In another aspect of the invention,

R¹ is COOH, C(O)OR^(o), C(O)NR^(c)R^(c), C(O)NR^(c)SO₂R^(c),C(O)NR^(c)SO₂NR^(c)R^(c), NR^(c)SO₂R^(c),

wherein R^(d) is methyl or H.

R² is

R_(j) is H or methyl.R^(h) is independently halo, NR^(c)R^(c), hydroxyC₁-C₄alkyl,hydroxyC₁-C₄alkoxy, —OC₁-C₃alkylOC₁-C₃alkyl, C₁-C₄alkyl or C₁-C₄alkoxy;a is 0, 1 or 2;

R³ is

X is O, S, NR¹⁶, CR¹⁶ ₂, or SO₂;

R¹⁵ is independently selected from the group consisting of phenyl, 5 or6-membered heteroaryl, heterocyclic, haloC₁-C₃alkyl, halo,haloC₁-C₃alkoxyC₀-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkoxyC₁-C₃alkyl,C₁-C₃alkoxyC₁-C₃alkoxy, C₁-C₃alkoxyC₃-C₅cycloalkyl, C₁-C₆alkyl,C₃-C₆cycloalkyl, C(O)R^(f), C(O)NR^(c) ₂, and hydroxyC₁-C₃alkyl;two non-adjacent R¹⁵ form a C₂-C₃ alkylene bridge;two adjacent R¹⁵ form a fused C₃-C₆cycloalkyl or 4, 5 or 6-memberedheterocyclic ring;or two R¹⁵ attached to the same carbon form ═O, a C₃-C₆cycloalkyl or 5or 6-membered heterocyclic ring,wherein the phenyl, heteroaryl, cycloalkyl or heterocyclic can beoptionally substituted with halo, or C₁-C₃alkyl;R¹⁶ is independently selected from the group consisting of H,haloC₁-C₃alkyl, halo, haloC₁-C₃alkoxyC₀-C₃alkyl, C₁-C₃alkoxy,C₁-C₃alkoxyC₁-C₃alkyl, C₁-C₆alkyl, C₃-C₆cycloalkyl, C(O)R^(f),C(O)NR^(c) ₂, S(O)₂R^(c), C(O)OR^(o) and hydroxyC₁-C₃alkyl;R^(c) is independently H or C₁-C₃alkyl optionally substituted with haloor C₁-C₃alkoxy;R¹⁰ is independently C₁-C₃alkyl optionally substituted with halo;R^(f) is independently H, C₁-C₃alkyl or C₃-C₄cycloalkyl, wherein thealkyl or cycloalkyl is optionally substituted with halo, C₁-C₃alkoxy, or4-6 membered heterocyclic;f is 0, 1 or 2;g is 0, or 1;j is independently 0, 1, or 2;or R³ is NR⁸R^(c), T-C₁-C₆alkyl, -T-aryl, -T-heteroaryl, T-heterocyclic,T-C₃-C₇cycloalkyl, wherein the alkyl, aryl, heteroaryl, heterocyclic,and cycloalkyl can be optionally substituted with halo, OR^(c), SR^(c),SO₂R^(c), haloC₁-C₃alkyl, haloC₁-C₃alkoxy, or C₁-C₃alkyl;R⁸ is H, C₁-C₆alkyl, arylC₁-C₆alkyl, or heterocyclic, wherein the alkyl,aryl or heterocyclic is optionally substituted with C₁-C₃alkoxy, orhaloC₁-C₃alkyl;T is independently —(CR^(a) ₂)—, —C(═CH₂)—, or —C(O)—;R^(a) is independently H, OR^(c), halo, or C₁-C₃alkyl, said alkyl isoptionally substituted with OH, C₁-C₃alkoxy, halo, or haloC₁-C₃alkyl;

R⁴ is

R^(b) and R^(s) are independently H, halo, haloC₁-C₃alkyl or C₁-C₃alkyl;R⁹ is H, C(O)NHR^(c), or methyl;i and I are independently 0, 1, 2, 3, 4 or 5; ande is 0, 1 or 2.

In a further aspect of the invention,

R¹ is COOH, C(O)NR^(c)SO₂R^(c), C(O)NR^(c)SO₂NR^(c)R^(c), or

wherein R^(d) is methyl or H.

R² is

R^(h) is independently halo, hydroxyC₁-C₄alkyl, hydroxyC₁-C₄alkoxy,—OC₁-C₃alkylOC₁-C₃alkyl, C₁-C₄alkyl or C₁-C₄alkoxy;a is 0, 1 or 2;

R³ is

X is NR¹⁶, CR¹⁶ ₂, or SO₂;

R¹⁵ is independently selected from the group consisting of phenyl, 5 or6-membered heteroaryl, heterocyclic, haloC₁-C₃alkyl, halo,haloC₁-C₃alkoxyC₀-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkoxyC₁-C₃alkyl,C₁-C₆alkyl, C₃-C₆cycloalkyl, C(O)R^(f), C(O)NR^(c) ₂, andhydroxyC₁-C₃alkyl;two non-adjacent R¹⁵ form a C₂-C₃ alkylene bridge;two adjacent R¹⁵ form a fused C₃-C₆cycloalkyl or 5 or 6-memberedheterocyclic ring;or two R¹⁵ attached to the same carbon form ═O, a C₃-C₆cycloalkyl or 5or 6-membered heterocyclic ring,wherein the phenyl, heteroaryl, cycloalkyl or heterocyclic can beoptionally substituted with halo, or C₁-C₃alkyl;R¹⁶ is independently selected from the group consisting of H,haloC₁-C₃alkyl, halo, haloC₁-C₃alkoxyC₀-C₃alkyl, C₁-C₃alkoxy,C₁-C₃alkoxyC₁-C₃alkyl, C₁-C₆alkyl, C₃-C₆cycloalkyl, C(O)R^(f),C(O)NR^(c) ₂, and hydroxyC₁-C₃alkyl;R^(c) is independently H or C₁-C₃alkyl optionally substituted with halo;R^(f) is independently H, C₁-C₃alkyl or C₃-C₄cycloalkyl;f is 0, 1 or 2;g is 0, or 1;j is independently 0, 1, or 2;or R³ is NR⁸R^(c), T-C₁-C₆alkyl, -T-aryl, -T-heteroaryl, T-heterocyclic,T-C₃-C₇cycloalkyl, wherein the alkyl, aryl, heteroaryl, heterocyclic,and cycloalkyl can be optionally substituted with halo, OR^(c),SO₂R^(c), haloC₁-C₃alkyl, haloC₁-C₃alkoxy, or C₁-C₃alkyl;R⁸ is H, C₁-C₆alkyl, arylC₁-C₆alkyl, or heterocyclic, wherein the alkyl,aryl or heterocyclic is optionally substituted with C₁-C₃alkoxy, orhaloC₁-C₃alkyl;T is independently —(CR^(a) ₂)—, —C(═CH₂)—, or —C(O)—;R^(a) is independently H, OR^(c), halo, or C₁-C₃alkyl, said alkyl isoptionally substituted with OH, C₁-C₃alkoxy, halo, or haloC₁-C₃alkyl;

R⁴ is

R^(b) and R^(s) are independently H, halo, haloC₁-C₃alkyl or C₁-C₃alkyl;R⁹ is H, C(O)NHR^(c), or methyl;i and I are independently 0, 1, 2, 3, 4 or 5; ande is 0, 1 or 2.

In one embodiment, R³ is

X is NR¹⁶, CR¹⁶ ₂, or SO₂;

R¹⁵ is independently selected from the group consisting of phenyl,heteroaryl group selected from oxadiazol, oxazol, triazol, thiazol, andisooxazol, haloC₁-C₃alkyl, halo, haloC₁-C₃alkoxyC₀-C₃alkyl, C₁-C₃alkoxy,C₁-C₃alkoxyC₁-C₃alkyl, C₁-C₆alkyl, C₃-C₆cycloalkyl, C(O)R^(f),C(O)NR^(c) ₂, and hydroxyC₁-C₃alkyl;two non-adjacent R¹⁵ form a C₂-C₃alkylene bridge;two adjacent R¹⁵ form a fused C₃-C₆cycloalkyl, furo or pyrano ring;or two R¹⁵ attached to the same carbon form ═O, a C₃-C₆cycloalkyl or 5or 6-membered heterocyclic ring, wherein the phenyl, heteroaryl,cycloalkyl or heterocyclic can be optionally substituted with halo, orC₁-C₃alkyl;

In another embodiment, R² is

R³ is phenyl or pyridyl, wherein the phenyl or pyridyl can be optionallysubstituted with halo, OR^(c), haloC₁-C₃alkyl, haloC₁-C₃alkoxy, orC₁-C₃alkyl;

In another embodiment, R³ is

R¹³ is independently H or halo;R¹⁵ is independently H or C₁-C₆alkyl;R¹⁸ is H or C₁-C₆alkyl; andr is independently 0, 1, or 2;

In yet another embodiment, R³ is

R¹⁵ is independently a 5-membered heteroaryl, haloC₁-C₆alkyl, halo,haloC₁-C₆alkoxy, C₁-C₆alkoxy, C₁-C₆alkoxyC₁-C₆alkyl, C₁-C₆alkyl,C₃-C₆cycloalkyl, C(O)N(R^(c))₂, or OH;j is independently 0, 1, 2, or 3.

In a further embodiment, R³ is

Ring B is a fused C₃-C₆cycloalkyl or fused 5 or 6-membered heterocyclic,wherein O is the heteroatom;

X is CH₂, NH or O.

In yet a further embodiment, R³ is

In yet one embodiment, R³ is

In yet a another embodiment, R³ is

In a further embodiment, R³ is

Ring B is a fused C₃-C₆cycloalkyl or fused 5 or 6-membered heterocyclic,whereinO is the heteroatom in the heterocyclic;

X is CH₂, or NH;

R¹³ is independently H, haloC₁-C₃alkyl, halo or C₁-C₃alkyl;R¹⁵ is independently H, haloC₁-C₃alkyl, halo, OH, C(O)R^(f),C₁-C₃alkoxy, C₁-C₃alkyl,or two R¹⁵ from the same carbon form =o;R^(f) is independently H, C₁-C₃alkyl or C₃-C₄cycloalkyl;r is independently 0, or 1; andj is independently 0, or 1.

In yet a further embodiment, R³ is

F is O or CH₂;

h is 0, 1 or 2;c is 0, 1 or 2; andd is 0, 1 or 2.In another aspect of the foregoing embodiments,

R¹ is COOH,

R² is

and R^(e) is halo.

In yet a further aspect of the invention for the foregoing embodiments,R⁴ is —CH₂—Y or —CH₂(CH₃)—Y, wherein Y is phenyl or cyclohexyloptionally substituted with haloC₁-C₃alkyl, haloC₂-C₃alkenyl, halo,C₃-C₄cycloalkyl, haloC₁-C₃alkoxy, C₁-C₃alkoxy, C₂-C₃alkenoxy,C₁-C₃alkyl, C₂-C₃alkenyl, amino, CN, OH, or SH. In one embodiment, R⁴ is—CH₂—Y or —CH₂(CH₃)—Y, wherein Y is phenyl or cyclohexyl, optionallysubstituted with CF₃, CHF₂, halo, cyclopropyl, OCF₃, OCH₃, methyl,amino, CN, OH, or SH.

In one embodiment,

R⁴ is

R^(b) is H, haloC₁-C₃alkyl or C₁-C₃alkyl;R^(g) is H, or methyl;R^(s) is H or halo;e is 0 or 1.

In one embodiment,

R⁴ is

R^(b) is independently H, halo, haloC₁-C₃alkyl or C₁-C₃alkyl;R^(g) is H, C(O)NHR^(c), or methyl;R^(c) is independently H or C₁-C₃alkyl optionally substituted with halo;

I is 0, 1, 2, 3, 4 or 5; and

e is 0, 1 or 2.In another embodiment, R⁴ is CH₂-cyclohexyl,

benzyl,

and R^(b) is H, haloC₁-C₃alkyl, haloC₂-C₃alkenyl, halo, haloC₁-C₃alkoxy,C₁-C₃alkoxy, C₁-C₃alkyl, C₂-C₃alkenyl, amino, CN, OH, or SH.In another embodiment, R⁴ is

R^(g) and R^(b) are independently H or methyl.In a further embodiment, R⁴ is

or

In one embodiment, R⁴ is

In a another embodiment, R⁴ is

In yet a further embodiment, R⁴ is

In another embodiment, R⁴ is

or

Specific examples of the compounds of the invention include, but notlimited to:

-   (R)-4-(1-cyclobutylethyl)amino)-2-(4-isopropylpyridin-2-yl)-7-methyl-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic    acid;-   4-{[(1R)-1-cyclobutylethyl]amino}-2-[4-(1-methylethyl)pyridin-2-yl]-3-[4-(trifluoromethyl)benzyl]-3H-imidazo[4,5-c]pyridine-6-carboxylic    acid;-   4-{[(1R)-1-cyclobutylethyl]amino}-2-(3-methylphenyl)-3-[4-(trifluoromethyl)benzyl]-3H-imidazo[4,5-c]pyridine-6-carboxylic    acid;-   4-{[(1R)-1-cyclobutylethyl]amino}-3-[(trans-4-methylcyclohexyl)methyl]-2-[4-(1-methylethyl)pyridin-2-yl]-3H-imidazo[4,5-c]pyridine-6-carboxylic    acid;-   3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   5-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,3,4-oxadiazol-2(3H)-one;-   3-{3-[(trans-4-methylcyclohexyl)methyl]-4-(3-methyl    phenyl)-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(3-chlorophenyl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   5-{4-(3-chlorophenyl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,3,4-oxadiazol-2(3H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-(4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-2-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-(hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(octahydro-4H-1,4-benzoxazin-4-yl)-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one;-   5-{4-(5-chloropyridin-3-yl)-2-(hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,3,4-oxadiazol-2(3H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2S)-2-(1-methoxy-1-methylethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   5-{4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,3,4-oxadiazol-2(3H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-(4aS,7aS)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(octahydro-4H-1,4-benzoxazin-4-yl)-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one;-   5-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(octahydro-4H-1,4-benzoxazin-4-yl)-3H-imidazo[4,5-c]pyridin-6-yl]-1,3,4-oxadiazol-2(3H)-one;-   5-{4-(5-chloropyridin-3-yl)-2-[(2S)-2-(1-methoxy-1-methylethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,3,4-oxadiazol-2(3H)-one;-   5-{4-(5-chloropyridin-3-yl)-2-(4aS,7aS)-hexahydrocyclopenta[b][1,4]oxazin-4(4a    H)-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,3,4-oxadiazol-2(3H)-one;-   5-{4-(5-chloropyridin-3-yl)-2-(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,3,4-oxadiazol-2(3H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(3R,5R)-3,5-dimethylmorpholin-4-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   5-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(octahydro-4H-1,4-benzoxazin-4-yl)-3H-imidazo[4,5-c]pyridin-6-yl]-1,3,4-oxadiazol-2(3H)-one;-   5-{4-(5-chloropyridin-3-yl)-2-[(3R,5R)-3,5-dimethylmorpholin-4-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,3,4-oxadiazol-2(3H)-one;-   5-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,3,4-oxadiazol-2(3H)-one;-   4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carboxylic    acid;-   3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-methylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(3S,5S)-3,5-dimethylmorpholin-4-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{7-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(octahydro-1H-cyclopenta[b]pyridin-1-yl)-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[6-(trifluoromethyl)-2-azabicyclo[3.1.0]hex-2-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-(3-ethylmorpholin-4-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(2-oxa-5-azabicyclo[4.1.0]hept-5-yl)-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4    Hy one;-   3-{4-(5-chloropyridin-3-yl)-2-(2,5-dimethylmorpholin-4-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(3-methyl-1,4-oxazepan-4-yl)-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[2-(1-methylethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carboxylic    acid;-   3-{4-(5-chloropyridin-3-yl)-2-[3-(2-fluorophenyl)morpholin-4-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[2-(1-methoxyethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[3-(2-fluorophenyl)morpholin-4-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-(2,3-dimethylpyrrolidin-1-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-(2-cyclopropylpyrrolidin-1-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{2-(2-tert-butylpyrrolidin-1-yl)-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{2-(5-azaspiro[3.4]oct-5-yl)-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[2-(1,1-dimethylpropyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[2-(4-methyl-1,2,5-oxadiazol-3-yl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(2R)-2-methylpiperidin-1-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;    and-   3-{4-(5-chloropyridin-3-yl)-2-[(2R,4R)-4-hydroxy-2-methylpyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;    or a stereoisomer thereof;    or a pharmaceutically acceptable salt thereof;    or a pharmaceutically acceptable salt of the stereoisomer thereof.

Other specific examples of the compounds of the invention include, butnot limited to:

-   3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[2-(4-methyl-1,2,5-oxadiazol-3-yl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   4-(5-chloropyridin-3-yl)-2-((4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic    acid;-   4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboxylic    acid;-   3-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(trans-2-methyl-5-phenylmorpholin-4-yl)-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2R,4R)-4-methoxy-2-methylpyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-(hexahydro-4H-furo[3,4-b][1,4]oxazin-4-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   1-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-N,N-dimethyl-D-prolinamide;-   1-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-N-ethyl-N-methyl-D-prolinamide;-   3-{4-(5-chloropyridin-3-yl)-2-[2-(3-ethyl-5-methylisoxazol-4-yl]-pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-{2-[(1-methylethoxy)methyl]pyrrolidin-1-yl}-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one;-   3-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-{2-[(trifluoromethoxy)methyl]pyrrolidin-1-yl}-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(2R)-2-methylpyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2S)-2-(difluoromethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-(trans-2,3-dimethylmorpholin-4-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(7-oxa-1-azaspiro[4.4]non-1-yl)-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one;-   3-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(8-oxa-1-azaspiro[4.5]dec-1-yl)-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-(hexahydro-2H-pyrano[4,3-b]pyridin-1(5H)-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[2-(1H-1,2,3-triazol-5-yl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[2-(1-methyl-1H-1,2,4-triazol-3-yl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[2-(1-methyl-1H-1,2,4-triazol-5-yl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(2S)-2-(1,3-thiazol-2-yl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[2-(3-methylisoxazol-5-yl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[2-(3,5-dimethylisoxazol-4-yl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[2-(3-methyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   1-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-N-ethyl-D-prolinamide;-   (5R)-4-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-1,5-dimethylpiperazin-2-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2R)-5-methoxy-2-methylpiperidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(3-methyl-1,1-dioxidothiomorpholin-4-yl)-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-(2-methoxy-7-azabicyclo[2.2.1]hept-7-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2S,4R)-4-methoxy-2-(1-methylethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2S,4R)-4-hydroxy-2-(1-methylethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2S,4R)-2-(fluoromethyl)-4-methoxypyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2R,4R)-2-(fluoromethyl)-4-methoxypyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-(4-(5-chloropyridin-3-yl)-3-(1-(trans-4-methylcyclohexyl)ethyl)-2-(R)-3-methylmorpholino)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one;-   (5R)-4-[4-(5-chloropyridin-3-yl)-3-[(1R)-1-(4-methylcyclohexyl)ethyl]-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-1,5-dimethylpiperazin-2-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2S,4R)-2-(fluoromethyl)-4-methoxypyrrolidin-1-yl]-3-[(1R)-1-(4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-(4-(5-chloropyridin-3-yl)-2-(2S,4R)-4-hydroxy-2-isopropylpyrrolidin-1-yl)-3-(R)-1-(trans-4-methylcyclohexyl)ethyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one;-   3-(4-(5-chloropyridin-3-yl)-2-(2R,4R)-4-methoxy-2-methylpyrrolidin-1-yl)-3-(R)-1-(trans-4-methylcyclohexyl)ethyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one;-   3-(4-(5-chloropyridin-3-yl)-2-(2R,4R)-4-hydroxy-2-methylpyrrolidin-1-yl)-3-(R)-1-(trans-4-methylcyclohexyl)ethyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one;-   3-{2-[(2R)-4-acetyl-2-methylpiperazin-1-yl]-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2R)-4-(cyclopropylcarbonyl)-2-methylpiperazin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{2-[(2R,6R)-4-acetyl-2,6-dimethylpiperazin-1-yl]-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2R,6R)-4-(cyclopropylcarbonyl)-2,6-dimethylpiperazin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[cyclopentyl(ethoxy)methyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   5-{4-(5-chloropyridin-3-yl)-2-[cyclopentyl(ethoxy)methyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,3,4-oxadiazol-2(3H)-one;-   3-(4-(5-chloropyridin-3-yl)-2-(1-ethoxyethyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one;-   3-(4-(5-chloropyridin-3-yl)-2-(1-ethoxypropyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one;-   3-(4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-2-(1-(2,2,2-trifluoroethoxy)propyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one;-   3-(4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-2-(1-propoxypropyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[ethoxy(phenyl)methyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2,4-difluorophenyl)(hydroxy)methyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2-fluorophenyl)(hydroxy)methyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-(1-hydroxy-2-methoxy-1-phenylethyl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-(4-(5-chloropyridin-3-yl)-2-(ethoxy(pyridin-2-yl)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one;-   3-(4-(5-chloropyridin-3-yl)-2-(ethoxy(pyridin-3-yl)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2-fluorophenyl)carbonyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[1-fluoro-1-(2-fluorophenyl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[1-(2,4-difluorophenyl)-1-fluoroethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(1-phenylethenyl)-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-(2-methoxy-1-phenylethyl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[1-(2-fluorophenyl)ethenyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;    and-   3-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(1-methylidenebutyl)-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one;    or a stereoisomer thereof;    or a pharmaceutically acceptable salt thereof;    or a pharmaceutically acceptable salt of the stereoisomer thereof.

Additional specific examples of the compounds of the invention include,but not limited to:

-   3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[methyl(2,2,2-trifluoroethyl)amino]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-(4-(5-chloropyridin-3-yl)-2-((trans-4-methoxytetrahydrofuran-3-yl)(methyl)amino)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[2-(1-methyl-1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   1-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-N-ethyl-N-methyl-L-prolinamide;-   3-{4-(5-chloropyridin-3-yl)-2-[(2-fluorophenyl)amino]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[2-(1-ethyl-1H-pyrazol-5-yl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[2-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[2-(3-methyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(6-oxa-1-azaspiro[3.3]hept-1-yl)-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2-methoxy-2-methylpropyl)(methyl)amino]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[2-(2-methyl-1,3-thiazol-4-yl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2-methoxyethyl)(methyl)amino]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[ethyl(2-methoxyethyl)amino]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   1-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-N,N-dimethyl-L-prolinamide;-   3-{4-(5-chloropyridin-3-yl)-2-[(2-methoxyethyl)(propyl)amino]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(1-pyridin-2-ylethyl)amino]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   1-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-N-ethyl-L-prolinamide;-   3-{2-[(2S,5S)-2,5-bis(methoxymethyl)pyrrolidin-1-yl]-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[cis-4-methoxy-2-methylpiperidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[trans-4-methoxy-2-methylpiperidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[cis-4-methoxy-2-methylpiperidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   (4aS,7aS)-4-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-1-methyloctahydro-2H-cyclopenta[b]pyrazin-2-one;-   4-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-5-ethyl-1-methylpiperazin-2-one;-   3-{4-(5-chloropyridin-3-yl)-2-(hexahydro-2H-pyrano[4,3-b]pyridin-1(5H)-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   benzyl    (4aR,8aR)-1-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl]octahydro-6H-pyrido[3,4-b][1,4]oxazine-6-carboxylate;-   3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(4aR,8aR)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{2-[(4aR,8aR)-6-benzyloctahydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl]-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-(2-hydroxy-7-azabicyclo[2.2.1]hept-7-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-(2-methoxy-7-azabicyclo[2.2.1]hept-7-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2S,4S)-4-hydroxy-4-methyl-2-(1-methylethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2S,4R)-4-methoxy-2-(methoxymethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-(3-hydroxyoctahydroquinolin-1(2H)-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2S,4R)-4-methoxy-2-(1-methoxycyclopropyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2R,4R)-4-methoxy-2-(1-methoxycyclopropyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(3-methylthiomorpholin-4-yl)-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2S,4R)-2-(difluoromethyl)-4-methoxypyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2S,4R)-4-ethoxy-2-(fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   (4aR,7aR)-4-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-1-ethyloctahydro-2H-cyclopenta[b]pyrazin-2-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2S,4R)-4-(2-methoxyethoxy)-2-(1-methylethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(trans)-5,5-difluorohexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(trans)-3-methylhexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2R,3R)-3-ethyl-2-methylmorpholin-4-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(trans)-6,6-difluorohexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-pyridin-2-ylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-(hexahydro-4H,5H-pyrano[4,3-b][1,4]oxazin-4-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(2-methylhexahydro-4H,5H-pyrano[4,3-b][1,4]oxazin-4-yl)-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(trans)-hexahydro-4H-furo[3,4-b][1,4]oxazin-4-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(trans)-6-fluorohexahydrocyclopenta[b][1,4]oxazin-4(4a    H)yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-(hexahydro-2H-cyclopenta[b][1,4]oxazepin-5(5aH)-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(2,2,3-trimethylmorpholin-4-yl)-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one;-   3-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(2-methyloctahydro-4H-1,4-benzoxazin-4-yl)-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one;-   3-{2-(benzylamino)-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2-methoxy-1-methylethyl)amino]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{2-[benzyl(methyl)amino]-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(2-methylhexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(2R,3R)-2,3,6-trimethylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2-methoxy-1-methylethyl)(methyl)amino]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(pyridin-2-ylamino)-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one;-   4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(pyridin-2-ylamino)-3H-imidazo[4,5-c]pyridine-6-carboxylic    acid;-   3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[methyl(phenyl)amino]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[methyl(phenyl)amino]-3H-imidazo[4,5-c]pyridine-6-carboxylic    acid;-   3-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(phenylamino)-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(1R    or    S)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-(4-(5-chloropyridin-3-yl)-3-(1-(trans-4-methylcyclohexyl)ethyl)-2-(R)-3-methylmorpholino)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one;-   (5R)-4-[4-(5-chloropyridin-3-yl)-3-[1-(trans-4-methylcyclohexyl)ethyl]-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-1,5-dimethylpiperazin-2-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2S,4R)-2-(fluoromethyl)-4-methoxypyrrolidin-1-yl]-3-[1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2S,4R)-4-hydroxy-2-(propan-2-yl)pyrrolidin-1-yl]-3-[1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2R,4R)-4-methoxy-2-methylpyrrolidin-1-yl]-3-[1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2R,4R)-4-hydroxy-2-methylpyrrolidin-1-yl]-3-[1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2R,6R)-2,6-dimethyl-4-(methylsulfonyl)piperazin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   ethyl    (3R,5R)-4-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-3,5-dimethylpiperazine-1-carboxylate;-   (3R,5R)-4-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-N-ethyl-3,5-dimethylpiperazine-1-carboxamide;-   3-{4-(5-chloropyridin-3-yl)-2-[(2R,6R)-2,6-dimethyl-4-propanoylpiperazin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2R,6R)-4-(cyclobutylcarbonyl)-2,6-dimethylpiperazin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{2-[(2R,6R)-4-butanoyl-2,6-dimethylpiperazin-1-yl]-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   methyl    (3R,5R)-4-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-3,5-dimethylpiperazine-1-carboxylate;-   1-methylethyl    (3R,5R)-4-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-3,5-dimethylpiperazine-1-carboxylate;-   (3R,5R)-4-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-3,5-dimethyl-N-propylpiperazine-1-carboxamide;-   (3R,5R)-4-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-3,5-dimethyl-N-(1-methylethyl)piperazine-1-carboxamide;-   3-{2-(4-acetyl-2,3-dimethylpiperazin-1-yl)-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[4-(cyclopropylcarbonyl)-2,3-dimethylpiperazin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2R,6R)-2,6-dimethyl-4-(2-methylpropanoyl)piperazin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-4-(cyclopropylcarbonyl)octahydro-1H-cyclopenta[b]pyrazin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{2-[(4aR,7aR)-4-acetyloctahydro-1H-cyclopenta[b]pyrazin-1-yl]-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-4-(difluoroacetyl)octahydro-1H-cyclopenta[b]pyrazin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-4-(cyclobutylcarbonyl)octahydro-1H-cyclopenta[b]pyrazin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   (3R,5R)-4-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-N,N,3,5-tetramethylpiperazine-1-carboxamide;-   (3R,5R)-4-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-N-ethyl-N,3,5-trimethylpiperazine-1-carboxamide;-   3-{4-(5-chloropyridin-3-yl)-2-{(2R,6R)-4-[(1-fluorocyclopropyl)carbonyl]-2,6-dimethylpiperazin-1-yl}-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-{(2R,6R)-4-[(2,2-difluorocyclopropyl)carbonyl]-2,6-dimethylpiperazin-1-yl}-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2R,6R)-4-(difluoroacetyl)-2,6-dimethylpiperazin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-{(2R,6R)-2,6-dimethyl-4-[(3-methyloxetan-3-yl)carbonyl]piperazin-1-yl}-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-{(2R,6R)-2,6-dimethyl-4-[(1-methylcyclopropyl)carbonyl]piperazin-1-yl}-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2R,6R)-2,6-dimethyl-4-(oxetan-3-ylcarbonyl)piperazin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(2R,6R)-4-(methoxyacetyl)-2,6-dimethylpiperazin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-(1-ethoxy-2-hydroxyethyl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-(1-ethoxy-2-methoxyethyl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[cyclopropyl(ethoxy)methyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[ethoxy(tetrahydro-2H-pyran-4-yl)methyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[cyclopropyl(2-methoxyethoxy)methyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-(4-(5-chloropyridin-3-yl)-2-(ethoxy(pyridin-2-yl)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[ethoxy(1,3-thiazol-4-yl)methyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[ethoxy(1-methyl-1H-pyrazol-3-yl)methyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[ethoxy(1,3-thiazol-4-yl)methyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[pyridin-2-yl(2,2,2-trifluoroethoxy)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(1R or    S)-1-fluoro-1-(3-fluoropyridin-2-yl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(1R or    S)-1-fluoro-1-(3-fluoropyridin-4-yl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(1R or    S)-1-fluoro-1-(3-methylpyridin-2-yl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(1R or    S)-1-fluoro-1-(pyridin-2-yl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-(1-fluoro-2-methoxy-1-methylethyl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[1-(3-fluoropyridin-2-yl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[1-(methoxymethyl)butyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(1-methylethenyl)-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-(2-methoxy-1-methylethyl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-(2-ethoxy-1-methylethyl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[1-methyl-2-(1-methylethoxy)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[1-(methoxymethyl)propyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[2-methoxy-1-(methoxymethyl)ethyl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[1-(methoxymethyl)-2-methylpropyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[4-(1-methylethyl)pyridin-2-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{7-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{7-chloro-4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-7-fluoro-2-[(4a R,7a    R)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-7-methoxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-7-methyl-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   4-(5-chloropyridin-3-yl)-7-(dimethylamino)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboxylic    acid;-   3-{4-(5-chloropyridin-3-yl)-2-[(2R or    S)-1-methoxypropan-2-yl]-3-[(1R or    S)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-N-(methylsulfonyl)-3H-imidazo[4,5-c]pyridine-6-carboxamide;-   4-(5-chloropyridin-3-yl)-N-(dimethylsulfamoyl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboxamide;-   4-(5-chloropyridin-3-yl)-N-methyl-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carboxamide;-   4-(5-chloropyridin-3-yl)-N,N-dimethyl-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carboxamide;-   N-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}methanesulfonamide;-   4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-6-(1H-tetrazol-5-yl)-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridine;-   5-{4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidi    n-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-2-methyl-1,2-dihydro-3H-1,2,4-triazol-3-one;-   5-{4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidi    n-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-2,4-dihydro-3H-1,2,4-triazol-3-one;-   4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-6-(1H-tetrazol-5-yl)-3H-imidazo[4,5-c]pyridine;-   methyl    4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carboxylate;-   ethyl    4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carboxylate;-   3-{4-(5-chloropyridin-3-yl)-2-[(S or    R)-cyclopropyl(ethoxy)methyl]-3-[(1R or    S)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(1 S or R)-1-ethoxyethyl]-3-[(1R or    S)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(1R or    S)-1-ethoxy-2-methoxyethyl]-3-[(1R or    S)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-{(2R)-4-[(1-fluorocyclopropyl)carbonyl]-2-methylpiperazin-1-yl}-3-[(1R    or    S)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4a    H)-yl]-3-[4-(trifluoromethyl)benzyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-ethylcyclohexyl)methyl]-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   5-{4-(5-chloropyridin-3-yl)-3-[(trans-4-ethylcyclohexyl)methyl]-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,3,4-oxadiazol-2(3H)-one;-   3-{4-(5-chloropyridin-3-yl)-3-[3-fluoro-4-(trifluoromethyl)benzyl]-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-[4-(5-chloropyridin-3-yl)-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-{[trans-4-(trifluoromethyl)cyclohexyl]methyl}-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-3-[(3-ethylcyclopentyl)methyl]-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-[5-chloro-2-(dimethylamino)pyridin-3-yl]-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloro-2-methylpyridin-3-yl)-2-[(4aS,7aS)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloro-2-methylpyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-[5-chloro-2-(2-hydroxyethoxy)pyridin-3-yl]-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloro-2-methoxypyridin-3-yl)-2-[(4aS,7aS)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloro-2-methoxypyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-[5-chloro-2-(2-methoxyethoxy)pyridin-3-yl]-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-[5-chloro-2-(2-methoxyethoxy)pyridin-3-yl]-2-[(4aS,7aS)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   5-chloro-3-{2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-4-yl}pyridin-2(1H)-one;-   3-{2-[(4a R,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4a    H)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-4-(5-methylpyridin-3-yl)-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{2-[(4aS,7aS)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-4-(5-methylpyridin-3-yl)-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-[5-chloro-2-(methylamino)pyridin-3-yl]-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   5-chloro-3-{3-[(trans-4-methylcyclohexyl)methyl]-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-4-yl}pyridin-2(1H)-one;-   3-{3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-4-pyrimidin-5-yl-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-4-(pyrazin-2-yl)-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-4-(pyridazin-4-yl)-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-4-(pyridazin-3-yl)-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[1-methyl-2-(methylsulfanyl)ethyl)-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[1-methyl-2-(methylsulfonyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-{1-[(methylsulfanyl)methyl]propyl}-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one;-   3-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-{1-[(methylsulfonyl)methyl]propyl}-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one;-   3-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-{2-methyl-1-[(methylsulfonyl)methyl]propyl}-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one;-   6-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}pyridin-2(1H)-one;-   3-{4-(cyclobutylmethoxy)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4-(1-cyclobutylethoxy)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one;    or a stereoisomer thereof;    or a pharmaceutically acceptable salt thereof;    or a pharmaceutically acceptable salt of the stereoisomer thereof.

Chemical Definitions

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. For example, C₁-C₁₀, as in “C₁-C₁₀alkyl” is defined to include groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or10 carbons in a linear or branched arrangement. For example, “C₁-C₁₀alkyl” specifically includes methyl, ethyl, n-propyl, i-propyl, n-butyl,t-butyl, i-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and so on.

When used in the phrases “alkylaryl”, “alkylcycloalkyl” and“alkylheterocyclyl” the term “alkyl” refers to the alkyl portion of themoiety and does not describe the number of atoms in the heterocyclylportion of the moiety. In an embodiment, if the number of carbon atomsis not specified, the “alkyl” of “alkylaryl”, “alkylcycloalkyl” and“alkylheterocyclyl” refers to C₁-C₁₂ alkyl and in a further embodiment,refers to C₁-C₆ alkyl.

The term “cycloalkyl” means a monocyclic, bicyclic or spirocyclicsaturated aliphatic hydrocarbon group having the specified number ofcarbon atoms. The cycloalkyl is optionally bridged (i.e., forming abicyclic moiety), for example with a methylene, ethylene or propylenebridge. The cycloalkyl may be fused with an aryl group such as phenyl,and it is understood that the cycloalkyl substituent is attached via thecycloalkyl group. For example, “cycloalkyl” includes cyclopropyl,methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl,cyclohexyl, and so on. “cycloalkyl” also includes cycloalkyl rings asdescribed above wherein ═CH₂ replaces two available hydrogens on thesame ring carbon atom.

The term “cyclenyl” means a monocyclic, bicyclic or spirocyclicunsaturated aliphatic hydrocarbon group having the specified number ofcarbon atoms. The cyclenyl is optionally bridged (i.e., forming abicyclic moiety), for example with a methylene, ethylene or propylenebridge. The cyclenyl may be fused with an aryl group such as phenyl, andit is understood that the cyclenyl substituent is attached via thecyclenyl group. For example, “cyclenyl” includes cyclopentenyl,cyclohexenyl and so on. “Cyclenyl” also includes cyclenyl rings asdescribed above wherein ═CH₂ replaces two available hydrogens on thesame ring carbon atom.

In an embodiment, if the number of carbon atoms is not specified,“alkyl” refers to C₁-C₁₋₂ alkyl and in a further embodiment, “alkyl”refers to C₁-C₆ alkyl. In an embodiment, if the number of carbon atomsis not specified, “cycloalkyl” refers to C₃-C₁₀ cycloalkyl and in afurther embodiment, “cycloalkyl” refers to C₃-C₇ cycloalkyl. In anembodiment, if the number of carbon atoms is not specified, “cyclenyl”refers to C₅-C₁₀ cyclenyl and in a further embodiment, “cyclenyl” refersto C₅-C₇ cyclenyl. In an embodiment, examples of “alkyl” include methyl,ethyl, n-propyl, i-propyl, n-butyl, t-butyl and i-butyl.

The term “alkylene” means a hydrocarbon diradical group having thespecified number of carbon atoms. For example, “alkylene” includes—CH₂—, —CH₂CH₂— and the like. In an embodiment, if the number of carbonatoms is not specified, “alkylene” refers to C₁-C₁₂ alkylene and in afurther embodiment, “alkylene” refers to C₁-C₆ alkylene.

If no number of carbon atoms is specified, the term “alkenyl” refers toa non-aromatic hydrocarbon radical, straight, branched or cyclic,containing from 2 to 10 carbon atoms and at least one carbon to carbondouble bond. Preferably one carbon to carbon double bond is present, andup to four non-aromatic carbon-carbon double bonds may be present. Thus,“C₂-C₆ alkenyl” means an alkenyl radical having from 2 to 6 carbonatoms. Alkenyl groups include ethenyl, propenyl, butenyl,2-methylbutenyl and cyclohexenyl. The straight, branched or cyclicportion of the alkenyl group may contain double bonds and may besubstituted if a substituted alkenyl group is indicated.

“Alkenylene” means a diradical group of an alkenyl group that is definedabove. For example, “alkenylene” includes —CH₂—CH₂—CH═CH—CH₂, —CH═CH—CH₂and the like.

The term “alkynyl” refers to a hydrocarbon radical straight, branched orcyclic, containing from 2 to 10 carbon atoms and at least one carbon tocarbon triple bond. Up to three carbon-carbon triple bonds may bepresent. Thus, “C₂-C₆ alkynyl” means an alkynyl radical having from 2 to6 carbon atoms. Alkynyl groups include ethynyl, propynyl, butynyl,3-methylbutynyl and so on. The straight, branched or cyclic portion ofthe alkynyl group may contain triple bonds and may be substituted if asubstituted alkynyl group is indicated.

In certain instances, substituents may be defined with a range ofcarbons that includes zero, such as (C₀-C₆)alkylene-aryl. If aryl istaken to be phenyl, this definition would include phenyl itself as wellas —CH₂Ph, —CH₂CH₂Ph, CH(CH₃)CH₂CH(CH₃)Ph, and so on.

“Aryl” is intended to mean any stable monocyclic, bicyclic or tricycliccarbon ring of up to 7 atoms in each ring, wherein at least one ring isaromatic. Examples of such aryl elements include phenyl, naphthyl,tetrahydronaphthyl, indanyl and biphenyl. In cases where the arylsubstituent is bicyclic and one ring is non-aromatic, it is understoodthat attachment is via the aromatic ring.

In one embodiment, “aryl” is an aromatic ring of 6 to 14 carbon atoms,and includes a carbocyclic aromatic group fused with a 5- or 6-memberedcycloalkyl group such as indan. Examples of carbocyclic aromatic groupsinclude, but are not limited to, phenyl, naphthyl, e.g. 1-naphthyl and2-naphthyl; anthracenyl, e.g. 1-anthracenyl, 2-anthracenyl;phenanthrenyl; fluorenonyl, e.g. 9-fluorenonyl, indanyl and the like.

The term heteroaryl, as used herein, represents a stable monocyclic,bicyclic or tricyclic ring of up to 7 atoms in each ring, wherein atleast one ring is aromatic and contains carbon and from 1 to 4heteroatoms selected from the group consisting of O, N and S. In anotherembodiment, the term heteroaryl refers to a monocyclic, bicyclic ortricyclic aromatic ring of 5- to 14-ring atoms of carbon and from one tofour heteroatoms selected from O, N, or S. As with the definition ofheterocycle below, “heteroaryl” is also understood to include theN-oxide derivative of any nitrogen-containing heteroaryl. In cases wherethe heteroaryl substituent is bicyclic and one ring is non-aromatic orcontains no heteroatoms, in one embodiment, the attachment is via theheteroatom containing aromatic ring, respectively.

Heteroaryl groups within the scope of this definition include but arenot limited to acridinyl, carbazolyl, cinnolinyl, quinoxalinyl,pyrrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl,benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl,pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,tetrahydroquinoline. Additional examples of heteroaryl include, but arenot limited to pyridyl, e.g., 2-pyridyl (also referred to as a-pyridyl),3-pyridyl (also referred to as β-pyridyl) and 4-pyridyl (also referredto as (γ-pyridyl); thienyl, e.g., 2-thienyl and 3-thienyl; furanyl,e.g., 2-furanyl and 3-furanyl; pyrimidyl, e.g., 2-pyrimidyl and4-pyrimidyl; imidazolyl, e.g., 2-imidazolyl; pyranyl, e.g., 2-pyranyland 3-pyranyl; pyrazolyl, e.g., 4-pyrazolyl and 5-pyrazolyl; thiazolyl,e.g., 2-thiazolyl, 4-thiazolyl and 5-thiazolyl; thiadiazolyl;isothiazolyl; oxazolyl, e.g., 2-oxazolyl, 4-oxazolyl and 5-oxazolyl;isoxazolyl; pyrrolyl; pyridazinyl; pyrazinyl and the like.

In an embodiment, “heteroaryl” may also include a “fused polycyclicaromatic”, which is a heteroaryl fused with one or more other heteroarylor nonaromatic heterocyclic ring. Examples include, quinolinyl andisoquinolinyl, e.g. 2-quinolinyl, 3-quinolinyl, 4-quinolinyl,5-quinolinyl, 6-quinolinyl, 7-quinolinyl and 8-quinolinyl,1-isoquinolinyl, 3-quinolinyl, 4-isoquinolinyl, 5-isoquinolinyl,6-isoquinolinyl, 7-isoquinolinyl and 8-isoquinolinyl; benzofuranyl, e.g.2-benzofuranyl and 3-benzofuranyl; dibenzofuranyl, e.g.2,3-dihydrobenzofuranyl; dibenzothiophenyl; benzothienyl, e.g.2-benzothienyl and 3-benzothienyl; indolyl, e.g. 2-indolyl and3-indolyl; benzothiazolyl, e.g., 2-benzothiazolyl; benzooxazolyl, e.g.,2-benzooxazolyl; benzimidazolyl, e.g. 2-benzoimidazolyl; isoindolyl,e.g. 1-isoindolyl and 3-isoindolyl; benzotriazolyl; purinyl;thianaphthenyl, pyrazinyl and the like.

“Heterocyclyl” means a non-aromatic saturated monocyclic, bicyclic,tricyclic or spirocyclic ring system comprising up to 7 atoms in eachring, or contains 3 to 14, or 5 to 10 ring atoms, in which one or moreof the atoms in the ring system is an element other than carbon, forexample, nitrogen, oxygen, phosphor or sulfur, alone or in combination.There are no adjacent oxygen and/or sulfur atoms present in the ringsystem. Preferred heterocyclyls contain about 5 to about 6 ring atoms.The heterocycle may be fused with an aromatic aryl group such as phenylor heterocyclenyl. The heterocyclyl is optionally bridged (i.e., forminga bicyclic moiety), for example with a methylene, ethylene or propylenebridge. The prefix aza, oxa or thia before the heterocyclyl root namemeans that at least a nitrogen, oxygen or sulfur atom, respectively, ispresent as a ring atom. The nitrogen or sulfur atom of the heterocyclylcan be optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclylrings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl,tetrahydrothiophenyl, lactam, lactone, and the like. “Heterocyclyl” alsoincludes heterocyclyl rings as described above wherein ═O replaces twoavailable hydrogens on the same ring carbon atom. An example of such amoiety is pyrrolidone:

In describing the heteroatoms contained in a specified heterocyclylgroup, the expression, “having one to x heteroatoms selected from thegroup of N, O, P and S” (wherein x is a specified integer), for example,means that each heteroatom in the specified heterocyclyl isindependently selected from the specified selection of heteroatoms.Attachment of a heterocyclyl substituent can occur via a carbon atom orvia a heteroatom. In cases where the heterocyclyl substituent isbicyclic and one ring is aromatic, unsaturated and/or contains noheteroatoms, in one embodiment, the attachment is via the heteroatomcontaining non-aromatic saturated ring.

“Heterocyclenyl” means a non-aromatic unsaturated monocyclic, bicyclic,tricyclic or spirocyclic ring system comprising up to 7 atoms in eachring. Preferably, the heterocyclenyl contains 3 to 14, or 5 to 10 ringatoms, in which one or more of the atoms in the ring system is anelement other than carbon, for example nitrogen, oxygen or sulfur atom,alone or in combination, and which contains at least one carbon-carbondouble bond or carbon-nitrogen double bond. There are no adjacent oxygenand/or sulfur atoms present in the ring system. Preferred heterocyclenylrings contain about 5 to about 6 ring atoms. The heterocyclenyl isoptionally bridged (i.e., forming a bicyclic moiety), for example with amethylene, ethylene or propylene bridge. The prefix aza, oxa or thiabefore the heterocyclenyl root name means that at least a nitrogen,oxygen, phosphor or sulfur atom respectively is present as a ring atom.The nitrogen or sulfur atom of the heterocyclenyl can be optionallyoxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.Non-limiting examples of suitable heterocyclenyl groups include1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl,1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl,2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl,dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl,dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl,fluorodihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl,dihydrothiopyranyl, and the like. “Heterocyclenyl” also includesheterocyclenyl rings as described above wherein ═O replaces twoavailable hydrogens on the same ring carbon atom. An example of such amoiety is pyrrolidinone:

In describing the heteroatoms contained in a specified heterocyclenylgroup, the expression, “having one to x heteroatoms selected from thegroup of N, O, P and S” (wherein x is an a specified integer), forexample, means that each heteroatom in the specified heterocyclenyl isindependently selected from the specified selection of heteroatoms. Incases where the heterocyclenyl substituent is bicyclic and one ring isaromatic, saturated and/or contains no heteroatoms, in one embodiment,the attachment is via the heteroatom containing non-aromatic unsaturatedring.

It should also be noted that tautomeric forms such as, for example, themoieties:

are considered equivalent in certain embodiments of this invention.

An “alkylaryl group” is an alkyl group substituted with an aryl group,for example, a phenyl group. Suitable aryl groups are described hereinand suitable alkyl groups are described herein. The bond to the parentmoiety is through the aryl group.

An “alkylheteroaryl group” is an alkyl group substituted with aheteroaryl group. Suitable heteroaryl groups are described herein andsuitable alkyl groups are described herein. The bond to the parentmoiety is through the heteroaryl group.

An “alkylheterocyclyl group” is an alkyl group substituted with aheterocyclyl group. Suitable heterocyclyl groups are described hereinand suitable alkyl groups are described herein. The bond to the parentmoiety is through the heterocyclyl group.

An “alkylheterocyclenyl group” is an alkyl group substituted with aheterocyclenyl group. Suitable heterocyclenyl groups are describedherein and suitable alkyl groups are described herein. The bond to theparent moiety is through the heterocyclenyl group.

An “alkylcycloalkyl group” is an alkyl group substituted with acycloalkyl group. Suitable cycloalkyl groups are described herein andsuitable alkyl groups are described herein. The bond to the parentmoiety is through the cycloalkyl group.

An “arylalkyl group” is an aryl group substituted with an alkyl group.Suitable aryl groups are described herein and suitable alkyl groups aredescribed herein. The bond to the parent moiety is through the alkylgroup.

A “heteroarylalkyl group” is a heteroaryl group substituted with analkyl group. Suitable heteroaryl groups are described herein andsuitable alkyl groups are described herein. The bond to the parentmoiety is through the alkyl group.

A “heterocyclylalkyl group” is a heterocyclyl group substituted with analkyl group. Suitable heterocyclyl groups are described herein andsuitable alkyl groups are described herein. The bond to the parentmoiety is through the alkyl group.

A “heterocyclenylalkyl group” is a heterocyclenyl group substituted withan alkyl group. Suitable heterocyclenyl groups are described herein andsuitable alkyl groups are described herein. The bond to the parentmoiety is through the alkyl group.

A “cycloalkylalkyl group” is a cycloalkyl group substituted with analkyl group. Suitable cycloalkyl groups are described herein andsuitable alkyl groups are described herein. The bond to the parentmoiety is through the alkyl group.

An “aryloxy group” is an aryl group that is attached to a compound viaan oxygen (e.g., phenoxy).

An “alkoxy group” (alkyloxy), as used herein, is a straight chain orbranched C₁-C₁₂ or cyclic C₃-C₁₂ alkyl group that is connected to acompound via an oxygen atom. Examples of alkoxy groups include but arenot limited to methoxy, ethoxy and propoxy.

An “arylalkoxy group” (arylalkyloxy) is an arylalkyl group that isattached to a compound via an oxygen on the alkyl portion of thearylalkyl (e.g., phenyl methoxy).

An “arylamino group” as used herein, is an aryl group that is attachedto a compound via a nitrogen.

An “alkylamino group” as used herein, is an alkyl group that is attachedto a compound via a nitrogen.

A “dialkylamino group” as used herein, is two alkyl groups that areattached to a compound via a nitrogen.

As used herein, an “arylalkylamino group” is an arylalkyl group that isattached to a compound via a nitrogen on the alkyl portion of thearylalkyl.

An “alkylsulfonyl group” as used herein, is an alkyl group that isattached to a compound via the sulfur of a sulfonyl group.

A “haloalkyl group” as used herein, is an alkyl group substituted with ahalo group, which is attached to a compound via the alkyl group.

A “hydroxyalkyl group” as used herein, is an alkyl group substitutedwith a hydroxy group, which is attached to a compound via the alkylgroup.

When a moiety is referred to as “unsubstituted” or not referred to as“substituted” or “optionally substituted”, it means that the moiety doesnot have any substituents. When a moiety is referred to as substituted,it denotes that any portion of the moiety that is known to one skilledin the art as being available for substitution can be substituted. Thephrase a group “optionally substituted with” substituent1, etc., orsubstituent2; substituent selected from the group consisting ofsubstituent1, etc., and substituent2, means the group can be optionallysubstituted with one or more of the substituents, one substituent, twosubstituents, three substituents, four substituents or fivesubstituents. For example, the substitutable group can be a hydrogenatom that is replaced with a group other than hydrogen (i.e., asubstituent group). Multiple substituent groups can be present. Whenmultiple substituents are present, the substituents can be the same ordifferent and substitution can be at any of the substitutable sites.Such means for substitution are well known in the art. For purposes ofexemplification, which should not be construed as limiting the scope ofthis invention, some examples of groups that are substituents are:alkyl, alkenyl or alkynyl groups (which can also be substituted, withone or more substituents), alkoxy groups (which can be substituted), ahalogen or halo group (F, Cl, Br, I), hydroxy, nitro, oxo, —CN, —COH,—COOH, amino, azido, N-alkylamino or N,N-dialkylamino (in which thealkyl groups can also be substituted), N-arylamino or N,N-diarylamino(in which the aryl groups can also be substituted), esters (—C(O)—OR,where R can be a group such as alkyl, aryl, etc., which can besubstituted), ureas (—NHC(O)—NHR, where R can be a group such as alkyl,aryl, etc., which can be substituted), carbamates (—NHC(O)—OR, where Rcan be a group such as alkyl, aryl, etc., which can be substituted),sulfonamides (—NHS(O)₂R, where R can be a group such as alkyl, aryl,etc., which can be substituted), alkylsulfonyl (which can besubstituted), aryl (which can be substituted), cycloalkyl (which can besubstituted) alkylaryl (which can be substituted), alkylheterocyclyl(which can be substituted), alkylcycloalkyl (which can be substituted),and aryloxy.

It should also be noted that any carbon as well as heteroatom withunsatisfied valences in the text, schemes, examples and Tables herein isassumed to have the sufficient number of hydrogen atom(s) to satisfy thevalences.

Although symbols/letters (i.e., B, F, K, U, W and Y) for substituentsunder Formula I may coincide with the abbreviated name for a chemicalelement, the definitions for the substituents under Formula I should beused.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in organic Synthesis(1991), Wiley, New York.

When any variable (e.g., aryl, heterocycle, R², etc.) occurs more thanone time in any constituent or in Formula I, its definition on eachoccurrence is independent of its definition at every other occurrence.

As used herein, “a,” an” and “the” include singular and plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “an active agent” or “a pharmacologically active agent”includes a single active agent as well a two or more different activeagents in combination, reference to “a carrier” includes mixtures of twoor more carriers as well as a single carrier, and the like.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

Isotopes

In the compounds of generic Formula I, the atoms may exhibit theirnatural isotopic abundances, or one or more of the atoms may beartificially enriched in a particular isotope having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number predominantly found in nature. The present invention ismeant to include all suitable isotopic variations of the compounds ofgeneric Formula I. For example, different isotopic forms of hydrogen (H)include protium (1H) and deuterium (2H). Protium is the predominanthydrogen isotope found in nature. Enriching for deuterium may affordcertain therapeutic advantages, such as increasing in vivo half-life orreducing dosage requirements, or may provide a compound useful as astandard for characterization of biological samples.Isotopically-enriched compounds within generic Formula I can be preparedwithout undue experimentation by conventional techniques well known tothose skilled in the art or by processes analogous to those described inthe Schemes and Examples herein using appropriate isotopically-enrichedreagents and/or intermediates.

Certain isotopically-labelled compounds of Formula (I) (e.g., thoselabeled with ³H and ¹⁴C) are useful in compound and/or substrate tissuedistribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C)isotopes are particularly preferred for their ease of preparation anddetectability. Certain isotopically-labelled compounds of Formula (I)can be useful for medical imaging purposes. For instance those compoundslabeled with positron-emitting isotopes like ¹¹C or ¹⁸F can be usefulfor application in Positron Emission Tomography (PET) and those labeledwith gamma ray emitting isotopes like ¹²³I can be useful for applicationin Single Photon Emission Computed Tomography (SPECT). Additionally,isotopic substitution of a compound at a site where epimerization occursmay slow or reduce the epimerization process and thereby retain the moreactive or efficacious form of the compound for a longer period of time.

Stereochemistry

When structures of the same constitution differ in respect to thespatial arrangement of certain atoms or groups, they are stereoisomers,and the considerations that are significant in analyzing theirinterrelationships are topological. If the relationship between twostereoisomers is that of an object and its nonsuperimposable mirrorimage, the two structures are enantiomeric, and each structure is saidto be chiral. Stereoisomers also include diastereomers, cis-transisomers and conformational isomers. Diastereoisomers can be chiral orachiral, and are not mirror images of one another. Cis-trans isomersdiffer only in the positions of atoms relative to a specified planes incases where these atoms are, or are considered as if they were, parts ofa rigid structure. Conformational isomers are isomers that can beinterconverted by rotations about formally single bonds. Examples ofsuch conformational isomers include cyclohexane conformations with chairand boat conformers, carbohydrates, linear alkane conformations withstaggered, eclipsed and gauche conformers, etc. See J. Org. Chem. 35,2849 (1970).

Many organic compounds exist in optically active forms having theability to rotate the plane of plane-polarized light. In describing anoptically active compound, the prefixes D and L or R and S are used todenote the absolute configuration of the molecule about its chiralcenter(s). The prefixes d and I or (+) and (−) are employed to designatethe sign of rotation of plane-polarized light by the compound, with (−)or meaning that the compound is levorotatory. A compound prefixed with(+) or d is dextrorotatory. For a given chemical structure, enantiomersare identical except that they are non-superimposable mirror images ofone another. A mixture of enantiomers is often called an enantiomericmixture. A 50:50 mixture of enantiomers is referred to as a racemicmixture. Many of the compounds described herein can have one or morechiral centers and therefore can exist in different enantiomeric forms.If desired, a chiral carbon can be designated with an asterisk (*). Whenbonds to the chiral carbon are depicted as straight lines in theFormulas of the invention, it is understood that both the (R) and (S)configurations of the chiral carbon, and hence both enantiomers andmixtures thereof, are embraced within the Formula. As is used in theart, when it is desired to specify the absolute configuration about achiral carbon, one of the bonds to the chiral carbon can be depicted asa wedge (bonds to atoms above the plane) and the other can be depictedas a series or wedge of short parallel lines (bonds to atoms below theplane). The Cahn-Inglod-Prelog system can be used to assign the (R) or(S) configuration to a chiral carbon.

When the compounds of the present invention contain one chiral center,the compounds exist in two enantiomeric forms and the present inventionincludes both enantiomers and mixtures of enantiomers, such as thespecific 50:50 mixture referred to as a racemic mixtures. Theenantiomers can be resolved by methods known to those skilled in theart, such as formation of diastereoisomeric salts which may beseparated, for example, by crystallization (see, CRC Handbook of OpticalResolutions via Diastereomeric Salt Formation by David Kozma (CRC Press,2001)); formation of diastereoisomeric derivatives or complexes whichmay be separated, for example, by crystallization, gas-liquid or liquidchromatography; selective reaction of one enantiomer with anenantiomer-specific reagent, for example enzymatic esterification; orgas-liquid or liquid chromatography in a chiral environment, for exampleon a chiral support for example silica with a bound chiral ligand or inthe presence of a chiral solvent. It will be appreciated that where thedesired enantiomer is converted into another chemical entity by one ofthe separation procedures described above, a further step is required toliberate the desired enantiomeric form. Alternatively, specificenantiomers may be synthesized by asymmetric synthesis using opticallyactive reagents, substrates, catalysts or solvents, or by converting oneenantiomer into the other by asymmetric transformation.

Designation of a specific absolute configuration at a chiral carbon ofthe compounds of the invention is understood to mean that the designatedenantiomeric form of the compounds is in enantiomeric excess (ee) or inother words is substantially free from the other enantiomer. Forexample, the “R” forms of the compounds are substantially free from the“5” forms of the compounds and are, thus, in enantiomeric excess of the“S” forms. Conversely, “S” forms of the compounds are substantially freeof “R” forms of the compounds and are, thus, in enantiomeric excess ofthe “R” forms. Enantiomeric excess, as used herein, is the presence of aparticular enantiomer at greater than 50%. In a particular embodimentwhen a specific absolute configuration is designated, the enantiomericexcess of depicted compounds is at least about 90%.

When a compound of the present invention has two or more chiral carbonsit can have more than two optical isomers and can exist indiastereoisomeric forms. For example, when there are two chiral carbons,the compound can have up to 4 optical isomers and 2 pairs of enantiomers((S,S)/(R,R) and (R,S)/(S,R)). The pairs of enantiomers (e.g.,(S,S)/(R,R)) are mirror image stereoisomers of one another. Thestereoisomers that are not mirror-images (e.g., (S,S) and (R,S)) arediastereomers. The diastereoisomeric pairs may be separated by methodsknown to those skilled in the art, for example chromatography orcrystallization and the individual enantiomers within each pair may beseparated as described above. The present invention includes eachdiastereoisomer of such compounds and mixtures thereof.

Solvates

One or more compounds of the invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. “Solvate” means a physicalassociation of a compound of this invention with one or more solventmolecules. This physical association involves varying degrees of ionicand covalent bonding, including hydrogen bonding. In certain instancesthe solvate will be capable of isolation, for example when one or moresolvent molecules are incorporated in the crystal lattice of thecrystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Non-limiting examples of suitable solvates includeethanolates, methanolates, and the like. Solvents to prepare solvatesinclude but are not limited to acetic acid, acetone, anisole, 1-butanol,2-butanol, butyl acetate, tert-butylmethyl ether, cumene, heptane,isobutyl acetate, methyl acetate, 3-methyl-1-butanol, methylethylketone, methylisobutyl ketone, 2-methyl-1-propanol, dimethyl sulfoxide,ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid,pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate andpropylene glycol. “Hydrate” is a solvate wherein the solvent molecule isH₂O.

One or more compounds of the invention may optionally be converted to asolvate. Preparation of solvates is generally known. Thus, for example,M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describethe preparation of the solvates of the antifungal fluconazole in ethylacetate as well as from water. Similar preparations of solvates,hemisolvate, hydrates and the like are described by E. C. van Tonder etal, AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham etal, Chem. Commun., 603-604 (2001). A typical, non-limiting, processinvolves dissolving the inventive compound in desired amounts of thedesired solvent (organic or water or mixtures thereof) at a higher thanambient temperature, and cooling the solution at a rate sufficient toform crystals which are then isolated by standard methods. Analyticaltechniques such as, for example I. R. spectroscopy, show the presence ofthe solvent (or water) in the crystals as a solvate (or hydrate).

The active compounds disclosed can also be prepared in any solid orliquid physical form. For example, the compound can be in a crystallineform, in amorphous form, and have any particle size. Furthermore, thecompound particles may be micronized, or may be agglomerated,particulate granules, powders, oils, oily suspensions or any other formof solid or liquid physical form.

The compounds of the present invention may also exhibit polymorphism.This invention further includes different polymorphs of the compounds ofthe present invention. The term “polymorph” refers to a particularcrystalline state of a substance, having particular physical propertiessuch as X-ray diffraction, IR spectra, melting point, and the like.

Pharmaceutically Acceptable Salts

The compounds of Formula I can form salts which are also within thescope of this invention. Reference to a compound of Formula I herein isunderstood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof Formula I contains both a basic moiety, such as, but not limited to apyridine or imidazole, and an acidic moiety, such as, but not limited toa carboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts arepreferred, although other salts are also useful. Salts of the compoundsof the Formula I may be formed, for example, by reacting a compound ofFormula I with an amount of acid or base, such as an equivalent amount,in a medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates,) and the like. Additionally,acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook ofPharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website).

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, zinc salts, salts with organic bases (forexample, organic amines) such as N-Me-D-glucamine, Choline,tromethamine, dicyclohexylamines, t-butyl amines, and salts with aminoacids such as arginine, lysine and the like. Basic nitrogen-containinggroups may be quarternized with agents such as lower alkyl halides (e.g.methyl, ethyl, and butyl chlorides, bromides and iodides), dialkylsulfates (e.g. dimethyl, diethyl, and dibutyl sulfates), long chainhalides (e.g. decyl, lauryl, and stearyl chlorides, bromides andiodides), aralkyl halides (e.g. benzyl and phenethyl bromides), andothers.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention.

Compounds of Formula I, and salts, solvates thereof, may exist in theirtautomeric form (for example, as an amide or imino ether). All suchtautomeric forms are contemplated herein as part of the presentinvention.

Pharmaceutical Compositions

The term “pharmaceutical composition” is also intended to encompass boththe bulk composition and individual dosage units comprised of more thanone (e.g., two) pharmaceutically active agents such as, for example, acompound of the present invention and an additional agent selected fromthe lists of the additional agents described herein, along with anypharmaceutically inactive excipients. The bulk composition and eachindividual dosage unit can contain fixed amounts of the afore-said “morethan one pharmaceutically active agents”. The bulk composition ismaterial that has not yet been formed into individual dosage units. Anillustrative dosage unit is an oral dosage unit such as tablets, pillsand the like. Similarly, the herein-described potential method oftreating a patient by administering a pharmaceutical composition of thepresent invention is also intended to encompass the administration ofthe afore-said bulk composition and individual dosage units.

Isolation of the compound at various stages of the reaction may beachieved by standard techniques such as, for example, filtration,evaporation of solvent and the like. Purification of the product and thelike, may also be performed by standard techniques such asrecrystallization, distillation, sublimation, chromatography, conversionto a suitable derivative. Such techniques are well known to thoseskilled in the art. The compounds of this invention may be analyzed fortheir composition and purity as well as characterized by standardanalytical techniques such as, for example, elemental analysis, NMR,mass spectroscopy, and IR spectra.

In another embodiment, this invention provides pharmaceuticalcompositions comprising the compounds of the invention as an activeingredient. The pharmaceutical compositions generally additionallycomprise a pharmaceutically acceptable carrier diluent, excipient orcarrier (collectively referred to herein as carrier materials).

In yet another embodiment, the present invention discloses methods forpreparing pharmaceutical compositions comprising the compounds as anactive ingredient. In the pharmaceutical compositions and methods of thepresent invention, the active ingredients will typically be administeredin admixture with suitable carrier materials suitably selected withrespect to the intended form of administration, i.e. oral tablets,capsules (either solid-filled, semi-solid filled or liquid filled),powders for constitution, oral gels, elixirs, dispersible granules,syrups, suspensions, and the like, and consistent with conventionalpharmaceutical practices. For example, for oral administration in theform of tablets or capsules, the active drug component may be combinedwith any oral non-toxic pharmaceutically acceptable inert carrier, suchas lactose, starch, sucrose, cellulose, magnesium stearate, dicalciumphosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms)and the like. Moreover, when desired or needed, suitable binders,lubricants, disintegrating agents and coloring agents may also beincorporated in the mixture. Powders and tablets may be comprised offrom about 5 to about 95 percent inventive composition. Suitable bindersinclude starch, gelatin, natural sugars, corn sweeteners, natural andsynthetic gums such as acacia, sodium alginate, carboxymethylcellulose,polyethylene glycol and waxes. Lubricants in these dosage forms includeboric acid, sodium benzoate, sodium acetate, sodium chloride, and thelike. Disintegrants include starch, methylcellulose, guar gum and thelike. Sweetening and flavoring agents and preservatives may also beincluded where appropriate. Some of the terms noted above, namelydisintegrants, diluents, lubricants, binders and the like, are discussedin more detail below.

Additionally, the compositions of the present invention may beformulated in sustained release form to provide the rate controlledrelease of any one or more of the components or active ingredients tooptimize the therapeutic effects. Suitable dosage forms for sustainedrelease include layered tablets containing layers of varyingdisintegration rates or controlled release polymeric matricesimpregnated with the active components and shaped in tablet form orcapsules containing such impregnated or encapsulated porous polymericmatrices.

Liquid form preparations include solutions, suspensions and emulsions.For example, water or water-propylene glycol solutions may be includedfor parenteral injections or sweeteners and pacifiers may be added fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier such as inert compressed gas, e.g.nitrogen.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides such as cocoa butter is first melted, and theactive ingredient is dispersed homogeneously therein by stirring orsimilar mixing. The molten homogeneous mixture is then poured intoconvenient sized molds, allowed to cool to solidify.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions may take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active components, e.g., aneffective amount to achieve the desired purpose.

The quantity of the inventive active composition in a unit dose ofpreparation may be generally varied or adjusted from about 1.0 milligramto about 1,000 milligrams, preferably from about 1.0 to about 500milligrams, and typically from about 1 to about 250 milligrams,according to the particular application. The actual dosage employed maybe varied depending upon the patient's age, sex, weight and severity ofthe condition being treated. Such techniques are well known to thoseskilled in the art.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

Generally, the human oral dosage form containing the active ingredientscan be administered 1 or 2 times per day. The amount and frequency ofthe administration will be regulated according to the judgment of theattending clinician. A generally recommended daily dosage regimen fororal administration may range from about 1.0 milligram to about 1,000milligrams per day, in single or divided doses.

Another aspect of this invention is a kit comprising a therapeuticallyeffective amount of at least one compound of Formula I, or apharmaceutically acceptable salt or solvate of said compound and apharmaceutically acceptable carrier, vehicle or diluent.

Yet another aspect of this invention is a kit comprising an amount of atleast one compound of Formula I, or a pharmaceutically acceptable saltor solvate of said compound and an amount of at least one anticancertherapy and/or anti-cancer agent described below, wherein the amounts ofthe two or more ingredients result in desired therapeutic effect.

Capsule—refers to a special container or enclosure made of methylcellulose, polyvinyl alcohols, or denatured gelatins or starch forholding or containing compositions comprising the active ingredients.Hard shell capsules are typically made of blends of relatively high gelstrength bone and pork skin gelatins. The capsule itself may containsmall amounts of dyes, opaquing agents, plasticizers and preservatives.

Tablet—refers to a compressed or molded solid dosage form containing theactive ingredients with suitable diluents. The tablet can be prepared bycompression of mixtures or granulations obtained by wet granulation, drygranulation or by compaction.

Oral gels—refer to the active ingredients dispersed or solubilized in ahydrophillic semi-solid matrix.

Powders for constitution refer to powder blends containing the activeingredients and suitable diluents which can be suspended in water orjuices.

Diluent—refers to substances that usually make up the major portion ofthe composition or dosage form. Suitable diluents include but are notlimited to sugars such as lactose, sucrose, mannitol and sorbitol;starches derived from wheat, corn, rice and potato; and celluloses suchas microcrystalline cellulose. The amount of diluent in the compositioncan range from about 10 to about 90% by weight of the total composition.

Disintegrants—refers to materials added to the composition to help itbreak apart (disintegrate) and release the medicaments. Suitabledisintegrants include but are not limited to modified starches such assodium carboxymethyl starch; methylcellulose, microcrystallinecelluloses and sodium croscarmellose; and sodium alginate. The amount ofdisintegrant in the composition can range from about 2 to about 10% byweight of the composition.

Lubricant—refers to a substance added to the dosage form to enable thetablet, granules, etc. after it has been compressed, to release from themold or die by reducing friction or wear. Suitable lubricants includemetallic stearates such as magnesium stearate, calcium stearate orpotassium stearate; stearic acid; high melting point waxes; and watersoluble lubricants such as high molecular weight polyethylene glycolsand d,l-leucine. Lubricants are usually added at the very last stepbefore compression, since they must be present on the surfaces of thegranules and in between them and the parts of the tablet press. Theamount of lubricant in the composition can range from about 0.2 to about5% by weight of the composition.

Glidents—materials that prevent caking and improve the flowcharacteristics of granulations, so that flow is smooth and uniform.Suitable glidents include silicon dioxide and talc. The amount ofglident in the composition can range from about 0.1% to about 5% byweight of the total composition.

Coloring agents—excipients that provide coloration to the composition orthe dosage form. Such excipients can include food grade dyes and foodgrade dyes adsorbed onto a suitable adsorbent such as clay or aluminumoxide. The amount of the coloring agent can vary from about 0.1 to about5% by weight of the composition.

Conventional methods for preparing tablets are known. Such methodsinclude dry methods such as direct compression and compression ofgranulation produced by compaction, or wet methods or other specialprocedures. Conventional methods for making other forms foradministration such as, for example, capsules, suppositories and thelike are also well known.

Method of Treatment

HDM2, Hdm2, hDM2, and hdm2 are all equivalent representations of theHuman Double Minute 2 protein. Likewise, MDM2, Mdm2, mDM2, and mdm2 areall equivalent representations mouse Double Minute 2 protein.

The compounds of Formula I can be inhibitors or antagonists of the Humanor Mouse Double Minute 2 protein interaction with p53 protein and it canbe activators of the p53 protein in cells. Furthermore, thepharmacological properties of the compounds of Formula I may be usefulto treat or prevent cancer, treat or prevent other disease statesassociated with abnormal cell proliferation, and treat or preventdiseases resulting from inadequate levels of p53 protein in cells.

Those skilled in the art will realize that the term “cancer” to be thename for diseases in which the body's cells become abnormal and dividewithout control.

Cancers that may be treated by the compounds, compositions and methodsof the invention include, but are not limited to: Cardiac: sarcoma(angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma,rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma(squamous cell, undifferentiated small cell, undifferentiated largecell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchialadenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma,leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma,leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma,glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel(adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma,leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma)colorectal; Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor[nephroblastoma], lymphoma, leukemia), bladder and urethra (squamouscell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate(adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonalcarcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cellcarcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver:hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenicsarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma and giant celltumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma,osteitis deformans), meninges (meningioma, meningiosarcoma,gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma,germinoma [pinealoma], glioblastoma multiform, oligodendroglioma,schwannoma, retinoblastoma, congenital tumors), spinal cordneurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus(endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervicaldysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecalcell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma),fallopian tubes (carcinoma), breast; Hematologic: blood (myeloidleukemia [acute and chronic], acute lymphoblastic leukemia, chroniclymphocytic leukemia, myeloproliferative diseases, multiple myeloma,myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma[malignant lymphoma]; Skin: malignant melanoma, basal cell carcinoma,squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi,lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands:neuroblastoma. Thus, the term “cancerous cell” as provided herein,includes a cell afflicted by any one of the above-identified conditions.

In one embodiment, cancers that may be treated by the compounds,compositions and methods of the invention include, but are not limitedto: lung cancer, pancreatic cancer, colon cancer, colorectal cancer,myeloid leukemias, acute myelogenous leukemia, chronic myelogenousleukemia, chronic myelomonocytic leukemia, thyroid cancer,myelodysplastic syndrome, bladder carcinoma, epidermal carcinoma,melanoma, breast cancer, prostate cancer, head and neck cancers, ovariancancer, brain cancers, cancers of mesenchymal origin, sarcomas,tetracarcinomas, neuroblastomas, kidney carcinomas, hepatomas,non-Hodgkin's lymphoma, multiple myeloma, and anaplastic thyroidcarcinoma.

In another embodiment, cancers that may be treated by the compounds,compositions and methods of the invention include, but are not limitedto: breast, prostate, colon, colorectal, lung, brain, testicular,stomach, pancrease, skin, small intestine, large intestine, throat, headand neck, oral, bone, liver, bladder, kidney, thyroid and blood.

In another embodiment, cancers that may be treated by the compounds,compositions and methods of the invention include breast, prostate,colon, ovary, endometrium and thyroid.

In another embodiment, cancers that may be treated by the compositionsand methods of the invention include acute myeloid leukemia (AML),liposarcoma, colorectal cancer, gastric cancer and melanoma.

In a further embodiment, cancers that may be treated by the compositionsand methods of the invention include hematological malignancies, forexample acute myeloid leukemia.

In a further embodiment, cancers that may be treated by the compositionsand methods of the invention include acute lymphoblastic leukemia (ALL),lymphoma, lung, breast and glioblastoma.

The compounds of the invention are also useful in preparing a medicamentthat may be useful in treating cancer. In one embodiment, the compoundsof the invention are for the potential treatment of cancer.

The compounds of Formula I may be useful to the treatment of a varietyof cancers, including, but not limited to: carcinoma, including, but notlimited to, of the bladder, breast, colon, rectum, endometrium, kidney,liver, lung, head and neck, esophagus, gall bladder, cervix, pancreas,prostrate, larynx, ovaries, stomach, uterus, sarcoma and thyroid cancer;

hematopoietic tumors of the lymphoid lineage, including leukemia, acutelymphocytic leukemia, chronic lymphocytic leukemia, acute lymphoblasticleukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma,non-Hodgkins lymphoma, hairy cell lymphoma, mantle cell lymphoma,myeloma, and Burkett's lymphoma;

hematopoetic tumors of myeloid lineage, including acute and chronicmyelogenous leukemias, myelodysplastic syndrome and promyelocyticleukemia;

tumors of mesenchymal origin, including fibrosarcoma andrhabdomyosarcoma;

tumors of the central and peripheral nervous system, includingastrocytoma, neuroblastoma, glioma, and schwannomas; and

other tumors, including melanoma, skin (non-melanomal) cancer,mesothelioma (cells), seminoma, teratocarcinoma, osteosarcoma,xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer andKaposi's sarcoma.

Due to the key role of p53 in the regulation of cellular apoptosis (celldeath), the compounds of Formula I could act as agent to induce celldeath which may be useful in the treatment of any disease process whichfeatures abnormal cellular proliferation eg, cancers of various originand tissue types, inflammation, immunological disorders.

Due to the key role of HDM2 and p53 in the regulation of cellularproliferation, the compounds of Formula I could act as reversiblecytostatic agents which may be useful in the treatment of any diseaseprocess which features abnormal cellular proliferation, inhibitors couldact as reversible cytostatic agents which may be useful in the treatmentof any disease process which features abnormal cell proliferation, e.g.,benign prostate hyperplasia, familial adenomatosis polyposis,neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis,psoriasis, glomerulonephritis, restenosis following angioplasty, orvascular surgery, hypertrophic scar formation, inflammatory boweldisease, transplantation rejection, endotoxic shock, and fungalinfections.

Compounds of Formula I may also be useful in the chemoprevention ofcancer. Chemoprevention is defined as inhibiting the development ofinvasive cancer by either blocking the initiating mutagenic event byblocking the progression of pre-malignant cells that have alreadysuffered an insult or inhibiting tumor relapse.

Compounds of Formula I may also be useful in inhibiting tumorangiogenesis and metastasis.

Another aspect of this invention is a potential method of treating amammal (e.g., human) having a disease or condition associated with HDM2by administering a therapeutically effective amount of at least onecompound of Formula I, or a pharmaceutically acceptable salt or solvateof said compound to the mammal.

The invention also provides a potential method of inhibiting one or moreHDM2 proteins in a patient in need thereof, comprising administering tothe patient a therapeutically effective amount of at least one compoundof claim 1 or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the present invention is a potential method oftreating, or slowing the progression of a disease associated with one ormore HDM2 proteins in a patient, comprising administering to a patientin need thereof, a therapeutically effective amount of at least onecompound of the present invention or a pharmaceutically acceptable saltor solvate thereof.

Another aspect of the present invention is a potential method oftreating, or slowing the progression of a disease associated withinadequate p53 levels in a patient, comprising administering to apatient in need thereof, a therapeutically effective amount of at leastone compound of the present invention or a pharmaceutically acceptablesalt or solvate thereof.

Yet another aspect of the present invention is a potential method oftreating one or more diseases associated with HDM2, comprisingadministering to a mammal in need of such treatment an amount of a firstcompound, which is a compound of the present invention, or apharmaceutically acceptable salt or solvate thereof; and an amount of atleast one second compound, the second compound being an anti-canceragent, wherein the amounts of the first compound and the second compoundresult in a therapeutic effect.

Another aspect of the present invention is a potential method oftreating one or more diseases associated with inadequate p53 levels,comprising administering to a mammal in need of such treatment an amountof a first compound, which is a compound of the present invention, or apharmaceutically acceptable salt or solvate thereof; and an amount of atleast one second compound, the second compound being an anti-canceragent, wherein the amounts of the first compound and the second compoundresult in a therapeutic effect.

Another aspect of the present invention is a potential method oftreating, or slowing the progression of, a disease associated with aHDM2 protein comprising administering to a patient in need thereof, atherapeutically effective amount of a pharmaceutical compositioncomprising in combination at least one pharmaceutically acceptablecarrier and at least one compound according to the present invention, ora pharmaceutically acceptable salt or solvate thereof.

Another aspect of the present invention is a potential method oftreating, or slowing the progression of, a disease associated withinadequate p53 levels in a patient, comprising administering to apatient in need thereof, a therapeutically effective amount of apharmaceutical composition comprising in combination at least onepharmaceutically acceptable carrier and at least one compound accordingto the present invention, or a pharmaceutically acceptable salt orsolvate thereof.

In one embodiment, the dosage is about 0.001 to 500 mg/kg of bodyweight/day of the compound of Formula I. In another embodiment, thedosage is about 0.01 to 25 mg/kg of body weight/day of a compound ofFormula I, or a pharmaceutically acceptable salt or solvate of saidcompound.

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the present inventioneffective in inhibiting the above-noted diseases and thus producing thedesired therapeutic, ameliorative, inhibitory or preventative effect.

“Patient” includes both human and animals.

“Mammal” means humans and other mammalian animals.

Combination Therapy

The instant compounds may also be useful in combination withtherapeutic, chemotherapeutic and anti-cancer agents. Combinations ofthe presently disclosed compounds with therapeutic, chemotherapeutic andanti-cancer agents are within the scope of the invention. Examples ofsuch agents can be found in Cancer Principles and Practice of Oncologyby V. T. Devita and S. Hellman (editors), 6^(th) edition (Feb. 15,2001), Lippincott Williams & Wilkins Publishers. A person of ordinaryskill in the art would be able to discern which combinations of agentswould be useful based on the particular characteristics of the drugs andthe cancer involved. Such agents include the following: estrogenreceptor modulators, androgen receptor modulators, retinoid receptormodulators, cytotoxic/cytostatic agents, antiproliferative agents,prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors andother angiogenesis inhibitors, HIV protease inhibitors, reversetranscriptase inhibitors, inhibitors of cell proliferation and survivalsignaling, bisphosphonates, aromatase inhibitors, siRNA therapeutics,γ-secretase inhibitors, agents that interfere with receptor tyrosinekinases (RTKs) and agents that interfere with cell cycle checkpoints.The instant compounds may also be useful when co-administered withradiation therapy. The compounds of the present invention can be presentin the same dosage unit as the anticancer agent or in separate dosageunits.

Another aspect of the present invention is a potential method oftreating one or more diseases associated with HDM2, comprisingadministering to a mammal in need of such treatment an amount of a firstcompound, which is a compound of the present invention, or apharmaceutically acceptable salt or solvate thereof; and an amount of atleast one second compound, the second compound being an anti-canceragent different from the compounds of the present invention, wherein theamounts of the first compound and the second compound result in atherapeutic effect.

Non-limiting examples of suitable anti-cancer agents include cytostaticagents, cytotoxic agents, targeted therapeutic agents (small molecules,biologics, siRNA and microRNA) against cancer and neoplastic diseases,

-   -   1) anti-metabolites (such as methoxtrexate, 5-fluorouracil,        gemcitabine, fludarabine, capecitabine);    -   2) alkylating agents, such as temozolomide, cyclophosphamide,    -   3) DNA interactive and DNA damaging agents, such as cisplatin,        oxaliplatin, doxorubicin,    -   4) Ionizing irradiation, such as radiation therapy,    -   5) topoisomerase II inhibitors, such as etoposide, doxorubicin,    -   6) topoisomerase I inhibitors, such as irinotecan, topotecan,    -   7) tubulin interacting agents, such as paclitaxel, docetaxel,        Abraxane, epothilones,    -   8) kinesin spindle protein inhibitors,    -   9) spindle checkpoint inhibitors,    -   10)Poly(ADP-ribose) polymerase (PARP) inhibitors, such as        olaparib, MK-4827 and veliparib    -   11)Matrix metalloprotease (MMP) inhibitors    -   12)Protease inhibitors, such as cathepsin D and cathepsin K        inhibitors    -   13)Proteosome or ubiquitination inhibitors, such as bortezomib,    -   14)Activator of mutant p53 to restore its wild-type p53 activity    -   15)Adenoviral-p53    -   16)Bcl-2 inhibitors, such as ABT-263    -   17)Heat shock protein (HSP) modulators, such as geldanamycin and        17-AAG    -   18)Histone deacetylase (HDAC) inhibitors, such as vorinostat        (SAHA),    -   19)sex hormone modulating agents,        -   a. anti-estrogens, such as tamoxifen, fulvestrant,        -   b. selective estrogen receptor modulators (SERM), such as            raloxifene,        -   c. anti-androgens, such as bicalutamide, flutamide        -   d. LHRH agonists, such as leuprolide,        -   e. 5a-reductase inhibitors, such as finasteride,        -   f. Cytochrome P450 C17 lyase (CYP450c17, also called            17a-hydroxylase/17,20 lysase) inhibitors, such as            Abiraterone acetate, VN/124-1, TAK-700        -   g. aromatase inhibitors, such as letrozole, anastrozole,            exemestane,    -   20)EGFR kinase inhibitors, such as geftinib, erlotinib, laptinib    -   21)dual erbB1 and erbB2 inhibitors, such as Lapatinib    -   22)multi-targeted kinases (serine/threonine and/or tyrosine        kinase) inhibitors,        -   a. ABL kinase inhibitors, imatinib and nilotinib, dasatinib        -   b. VEGFR-1, VEGFR-2, PDGFR, KDR, FLT, c-Kit, Tie2, Raf, MEK            and ERK inhibitors, such as sunitinib, sorafenib,            Vandetanib, pazopanib, PLX-4032, Axitinib, PTK787,            GSK-1120212        -   c. Polo-like kinase inhibitors        -   d. Aurora kinase inhibitors        -   e. JAK inhibitor        -   f. c-MET kinase inhibitors        -   g. Cyclin-dependent kinase inhibitors, such as CDK1 and CDK2            inhibitor SCH 727965        -   h. PI3K and mTOR inhibitors, such as GDC-0941, BEZ-235,            BKM-120 and AZD-8055        -   i. Rapamycin and its analogs, such as Temsirolimus,            everolimus, and deforolimus    -   23) and other anti-cancer (also know as anti-neoplastic) agents        include but are not limited to ara-C, adriamycin, cytoxan,        Carboplatin, Uracil mustard, Clormethine, Ifosfsmide, Melphalan,        Chlorambucil, Pipobroman, Triethylenemelamine,        Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,        Streptozocin, Dacarbazine, Floxuridine, Cytarabine,        6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate,        Pentostatine, Vinblastine, Vincristine, Vindesine, Vinorelbine,        Navelbine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin,        Epirubicin, teniposide, cytarabine, pemetrexed, Idarubicin,        Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase,        Teniposide, Ethinylestradiol, Diethylstilbestrol, Testosterone,        Prednisone, Fluoxymesterone, Dromostanolone propionate,        Testolactone, Megestrolacetate, Methylprednisolone,        Methyltestosterone, Prednisolone, Triamcinolone,        Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide,        Estramustine, Flutamide Medroxyprogesteroneacetate, Toremifene,        goserelin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine,        Mitotane, Mitoxantrone, Levamisole, Drolloxafine,        Hexamethylmelamine, Bexxar, Zevalin, Trisenox, Profimer,        Thiotepa, Altretamine, Doxil, Ontak, Depocyt, Aranesp, Neupogen,        Neulasta, Kepivance.    -   24)Farnesyl protein transferase inhibitors, such as, SARASAR™        (4-[2-[4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl-]-1-piperidinyl]-2-oxoethyl]-piperidinecarboxamide,        tipifarnib    -   25)interferons, such as Intron A, Peg-Intron,    -   26)anti-erbB1 antibodies, such as cetuximab, panitumumab,    -   27)anti-erbB2 antibodies, such as trastuzumab,    -   28)anti-CD52 antibodies, such as Alemtuzumab,    -   29)anti-CD20 antibodies, such as Rituximab    -   30)anti-CD33 antibodies, such as Gemtuzumab ozogamicin    -   31)anti-VEGF antibodies, such as Avastin,    -   32)TRIAL ligands, such as Lexatumumab, mapatumumab, and AMG-655    -   33)Anti-CTLA-4 antibodies, such as ipilimumab    -   34)antibodies against CTA1, CEA, CD5, CD19, CD22, CD30, CD44,        CD44V6, CD55, CD56, EpCAM, FAP, MHCII, HGF, IL-6, MUC1, PSMA,        TALE, TAG-72, TRAILR, VEGFR, IGF-2, FGF,    -   35)anti-IGF-1R antibodies, such as dalotuzumab (MK-0646) and        robatumumab (SCH 717454).

If formulated as a fixed dose such combination products employ thecompounds of this invention within the dosage range described herein andthe other pharmaceutically active agent or treatment within its dosagerange. Compounds of Formula I may also be administered sequentially withknown anticancer or cytotoxic agents when a combination formulation isinappropriate. The invention is not limited in the sequence ofadministration; compounds of Formula I may be administered eitherconcurrent with, prior to or after administration of the knownanticancer or cytotoxic agent. Such techniques are within the skills ofthe persons skilled in the art as well as attending physicians.

Accordingly, in an aspect, this invention includes combinationscomprising an amount of at least one compound of Formula I, or apharmaceutically acceptable salt or solvate thereof, and an amount ofone or more anti-cancer treatments and anti-cancer agents listed abovewherein the amounts of the compounds/treatments result in potentialtherapeutic effect.

“Estrogen receptor modulators” refers to compounds that interfere withor inhibit the binding of estrogen to the receptor, regardless ofmechanism. Examples of estrogen receptor modulators include, but are notlimited to, tamoxifen, raloxifene, idoxifene, LY353381, LY117081,toremifene, fulvestrant,4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate,4,4′-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.

“Androgen receptor modulators” refers to compounds which interfere orinhibit the binding of androgens to the receptor, regardless ofmechanism. Examples of androgen receptor modulators include finasterideand other 5a-reductase inhibitors, nilutamide, flutamide, bicalutamide,liarozole, and abiraterone acetate.

“Retinoid receptor modulators” refers to compounds which interfere orinhibit the binding of retinoids to the receptor, regardless ofmechanism. Examples of such retinoid receptor modulators includebexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid,a-difluoromethylornithine, ILX23-7553, trans-N-(4′-hydroxyphenyl)retinamide, and N-4-carboxyphenyl retinamide.

“Cytotoxic/cytostatic agents” refer to compounds which cause cell deathor inhibit cell proliferation primarily by interfering directly with thecell's functioning or inhibit or interfere with cell myosis, includingalkylating agents, tumor necrosis factors, intercalators, hypoxiaactivatable compounds, microtubule inhibitors/microtubule-stabilizingagents, inhibitors of mitotic kinesins, histone deacetylase inhibitors,inhibitors of kinases involved in mitotic progression, inhibitors ofkinases involved in growth factor and cytokine signal transductionpathways, antimetabolites, biological response modifiers,hormonal/anti-hormonal therapeutic agents, haematopoietic growthfactors, monoclonal antibody targeted therapeutic agents, topoisomeraseinhibitors, proteosome inhibitors, ubiquitin ligase inhibitors, andaurora kinase inhibitors.

Examples of cytotoxic/cytostatic agents include, but are not limited to,platinum coordinator compounds, sertenef, cachectin, ifosfamide,tasonermin, lonidamine, carboplatin, altretamine, prednimustine,dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin,temozolomide, heptaplatin, estramustine, improsulfan tosilate,trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin,satraplatin, profiromycin, cisplatin, irofulven, dexifosfamide,cis-aminedichloro(2-methyl-pyridine)platinum, benzylguanine,glufosfamide, GPX100, (trans, trans,trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(chloro)platinum(II)]tetrachloride, diarizidinylspermine, arsenic trioxide,1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin,idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin,pinafide, valrubicin, amrubicin, antineoplaston,3′-deamino-3′-morpholino-13-deoxo-10-hydroxycaminomycin, annamycin,galarubicin, elinafide,MEN10755,4-demethoxy-3-deamino-3-aziridinyl-4-methylsulphonyl-daunorubicin(see WO 00/50032).

An example of a hypoxia activatable compound is tirapazamine.

Examples of proteosome inhibitors include but are not limited tolactacystin and MLN-341 (Velcade).

Examples of microtubule inhibitors/microtubule-stabilising agentsinclude taxanes in general. Specific compounds include paclitaxel(Taxol®), vindesine sulfate,3′,4′-didehydro-4′-deoxy-8′-norvincaleukoblastine, docetaxol(Taxotere®), rhizoxin, dolastatin, mivobulin isethionate, auristatin,cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin,2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide,anhydrovinblastine,N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide,TDX258, the epothilones (see for example U.S. Pat. Nos. 6,284,781 and6,288,237) and BMS188797.

Some examples of topoisomerase inhibitors are topotecan, hycaptamine,irinotecan, rubitecan,6-ethoxypropionyl-3′,4′-O-exo-benzylidene-chartreusin,9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H)propanamine,1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:b,7]-indolizino[1,2b]quinoline-10,13(9H,15H)dione,lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350,BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane,2′-dimethylamino-2′-deoxy-etoposide, GL331,N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide,asulacrine, (5a, 5aB,8aa,9b)-9-[2-N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydroxy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9-hexohydrofuro(3′,′:6,7)naphtho(2,3-d)-1,3-dioxol-6-one,2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]-phenanthridinium,6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione,5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]acridin-6-one,N-1-[2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide,N-(2-(dimethylamino)ethyl)acridine-4-carboxamide,6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one,and dimesna.

Examples of inhibitors of mitotic kinesins, and in particular the humanmitotic kinesin KSP, are described in Publications WO03/039460,WO03/050064, WO03/050122, WO03/049527, WO03/049679, WO03/049678,WO04/039774, WO03/079973, WO03/099211, WO03/105855, WO03/106417,WO04/037171, WO04/058148, WO04/058700, WO04/126699, WO05/018638,WO05/019206, WO05/019205, WO05/018547, WO05/017190, US2005/0176776. Inan embodiment inhibitors of mitotic kinesins include, but are notlimited to inhibitors of KSP, inhibitors of MKLP1, inhibitors of CENP-E,inhibitors of MCAK and inhibitors of Rab6-KIFL.

Examples of “histone deacetylase inhibitors” include, but are notlimited to, SAHA, TSA, oxamflatin, PXD101, MG98 and scriptaid. Furtherreference to other histone deacetylase inhibitors may be found in thefollowing manuscript; Miller, T. A. et al. J. Med. Chem.46(24):5097-5116 (2003).

“Inhibitors of kinases involved in mitotic progression” include, but arenot limited to, inhibitors of aurora kinase, inhibitors of Polo-likekinases (PLK; in particular inhibitors of PLK-1), inhibitors of bub-1and inhibitors of bub-R1. An example of an “aurora kinase inhibitor” isVX-680.

“Antiproliferative agents” includes antisense RNA and DNAoligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001,and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin,doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine,cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed,paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed,nelzarabine, 2′-deoxy-2′-methylidenecytidine,2′-fluoromethylene-2′-deoxycytidine,N-[5-(2,3-dihydro-benzofuryl)sulfonylFN′-(3,4-dichlorophenyl)urea,N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L-manno-heptopyranosyl]adenine,aplidine, ecteinascidin, troxacitabine,4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b][1,4]thiazin-6-yl-(S)-ethyl]-2,5-thienoyl-L-glutamicacid, aminopterin, 5-fluorouracil, alanosine,11-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1,1′-diazatetracyclo(7.4.1.0.0)-tetradeca-2,4,6-trien-9-ylacetic acid ester, swainsonine, lometrexol, dexrazoxane, methioninase,2′-cyano-2′-deoxy-N4-palmitoyl-1-B-D-arabino furanosyl cytosine,3-aminopyridine-2-carboxaldehyde thiosemicarbazone and trastuzumab.

Examples of monoclonal antibody targeted therapeutic agents includethose therapeutic agents which have cytotoxic agents or radioisotopesattached to a cancer cell specific or target cell specific monoclonalantibody. Examples include Bexxar.

“HMG-CoA reductase inhibitors” refers to inhibitors of3-hydroxy-3-methylglutaryl-CoA reductase. Examples of HMG-CoA reductaseinhibitors that may be used include but are not limited to lovastatin(MEVACOR®; see U.S. Pat. Nos. 4,231,938, 4,294,926 and 4,319,039),simvastatin (ZOCOR®; see U.S. Pat. Nos. 4,444,784, 4,820,850 and4,916,239), pravastatin (PRAVACHOL®; see U.S. Pat. Nos. 4,346,227,4,537,859, 4,410,629, 5,030,447 and 5,180,589), fluvastatin (LESCOL®;see U.S. Pat. Nos. 5,354,772, 4,911,165, 4,929,437, 5,189,164,5,118,853, 5,290,946 and 5,356,896), atorvastatin (LIPITOR®; see U.S.Pat. Nos. 5,273,995, 4,681,893, 5,489,691 and 5,342,952) andcerivastatin (also known as rivastatin and BAYCHOL®; see U.S. Pat. No.5,177,080). The structural formulas of these and additional HMG-CoAreductase inhibitors that may be used in the instant methods aredescribed at page 87 of M. Yalpani, “Cholesterol Lowering Drugs”,Chemistry & Industry, pp. 85-89 (5 Feb. 1996) and U.S. Pat. Nos.4,782,084 and 4,885,314. The term HMG-CoA reductase inhibitor as usedherein includes all pharmaceutically acceptable lactone and open-acidforms (i.e., where the lactone ring is opened to form the free acid) aswell as salt and ester forms of compounds which have HMG-CoA reductaseinhibitory activity, and therefor the use of such salts, esters,open-acid and lactone forms is included within the scope of thisinvention.

“Prenyl-protein transferase inhibitor” refers to a compound whichinhibits any one or any combination of the prenyl-protein transferaseenzymes, including farnesyl-protein transferase (FPTase),geranylgeranyl-protein transferase type I (GGPTase-I), andgeranylgeranyl-protein transferase type-II (GGPTase-II, also called RabGGPTase).

Examples of prenyl-protein transferase inhibitors can be found in thefollowing publications and patents: WO 96/30343, WO 97/18813, WO97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO95/32987, U.S. Pat. No. 5,420,245, U.S. Pat. No. 5,523,430, U.S. Pat.No. 5,532,359, U.S. Pat. No. 5,510,510, U.S. Pat. No. 5,589,485, U.S.Pat. No. 5,602,098, European Patent Publ. 0 618 221, European PatentPubl. 0 675 112, European Patent Publ. 0 604 181, European Patent Publ.0 696 593, WO 94/19357, WO 95/08542, WO 95/11917, WO 95/12612, WO95/12572, WO 95/10514, U.S. Pat. No. 5,661,152, WO 95/10515, WO95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO 96/05529, WO96/06138, WO 96/06193, WO 96/16443, WO 96/21701, WO 96/21456, WO96/22278, WO 96/24611, WO 96/24612, WO 96/05168, WO 96/05169, WO96/00736, U.S. Pat. No. 5,571,792, WO 96/17861, WO 96/33159, WO96/34850, WO 96/34851, WO 96/30017, WO 96/30018, WO 96/30362, WO96/30363, WO 96/31111, WO 96/31477, WO 96/31478, WO 96/31501, WO97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO 97/02920, WO97/17070, WO 97/23478, WO 97/26246, WO 97/30053, WO 97/44350, WO98/02436, and U.S. Pat. No. 5,532,359. For an example of the role of aprenyl-protein transferase inhibitor on angiogenesis see European J. ofCancer, Vol. 35, No. 9, pp. 1394-1401 (1999).

“Angiogenesis inhibitors” refers to compounds that inhibit the formationof new blood vessels, regardless of mechanism. Examples of angiogenesisinhibitors include, but are not limited to, tyrosine kinase inhibitors,such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFR1) andFlk-1/KDR (VEGFR2), inhibitors of epidermal-derived, fibroblast-derived,or platelet derived growth factors, MMP (matrix metalloprotease)inhibitors, integrin blockers, interferon-α, interleukin-12, pentosanpolysulfate, cyclooxygenase inhibitors, including nonsteroidalanti-inflammatories (NSAIDs) like aspirin and ibuprofen as well asselective cyclooxy-genase-2 inhibitors like celecoxib and rofecoxib(PNAS, Vol. 89, p. 7384 (1992); JNCI, Vol. 69, p. 475 (1982); Arch.Opthalmol., Vol. 108, p. 573 (1990); Anat. Rec., Vol. 238, p. 68 (1994);FEBS Letters, Vol. 372, p. 83 (1995); Clin, Orthop. Vol. 313, p. 76(1995); J. Mol. Endocrinol., Vol. 16, p. 107 (1996); Jpn. J. Pharmacol.,Vol. 75, p. 105 (1997); Cancer Res., Vol. 57, p. 1625 (1997); Cell, Vol.93, p. 705 (1998); Intl. J. Mol. Med., Vol. 2, p. 715 (1998); J. Biol.Chem., Vol. 274, p. 9116 (1999)), steroidal anti-inflammatories (such ascorticosteroids, mineralocorticoids, dexamethasone, prednisone,prednisolone, methylpred, betamethasone), carboxyamidotriazole,combretastatin A-4, squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol,thalidomide, angiostatin, troponin-1, angiotensin II antagonists (seeFernandez et al., J. Lab. Clin. Med. 105:141-145 (1985)), and antibodiesto VEGF (see, Nature Biotechnology, Vol. 17, pp. 963-968 (October 1999);Kim et al., Nature, 362, 841-844 (1993); WO 00/44777; and WO 00/61186).

Other examples of angiogenesis inhibitors include, but are not limitedto, endostatin, ukrain, ranpirnase,IM862,5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate,acetyldinanaline,5-amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]methyl]-1H-1,2,3-triazole-4-carboxamide,CM101, squalamine, combretastatin, RPI4610, NX31838, sulfatedmannopentaose phosphate,7,7-(carbonyl-bis[imino-N-methyl-4,2-pyrrolocarbonylimino[N-methyl-4,2-pyrrole]-carbonylimino]-bis-(1,3-naphthalenedisulfonate), and 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone(SU5416).

Other therapeutic agents that modulate or inhibit angiogenesis and mayalso be used in combination with the compounds of the instant inventioninclude agents that modulate or inhibit the coagulation and fibrinolysissystems (see review in Clin. Chem. La. Med. 38:679-692 (2000)). Examplesof such agents that modulate or inhibit the coagulation and fibrinolysispathways include, but are not limited to, heparin (see Thromb. Haemost.80:10-23 (1998)), low molecular weight heparins and carboxypeptidase Uinhibitors (also known as inhibitors of active thrombin activatablefibrinolysis inhibitor [TAFIa]) (see Thrombosis Res. 101:329-354(2001)). TAFIa inhibitors have been described in U.S. Ser. Nos.60/310,927 (filed Aug. 8, 2001) and 60/349,925 (filed Jan. 18, 2002).

“Agents that interfere with cell cycle checkpoints” refer to compoundsthat inhibit protein kinases that transduce cell cycle checkpointsignals, thereby sensitizing the cancer cell to DNA damaging agents.Such agents include inhibitors of ATR, ATM, the CHK11 and CHK12 kinasesand cdk and cdc kinase inhibitors and are specifically exemplified by7-hydroxystaurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032.

“Agents that interfere with receptor tyrosine kinases (RTKs)” refer tocompounds that inhibit RTKs and therefore mechanisms involved inoncogenesis and tumor progression. Such agents include inhibitors ofc-Kit, Eph, PDGF, Flt3 and c-Met. Further agents include inhibitors ofRTKs as described by Bume-Jensen and Hunter, Nature, 411:355-365, 2001.

“Inhibitors of cell proliferation and survival signalling pathway” referto compounds that inhibit signal transduction cascades downstream ofcell surface receptors. Such agents include inhibitors ofserine/threonine kinases (including but not limited to inhibitors of Aktsuch as described in WO 02/083064, WO 02/083139, WO 02/083140, US2004-0116432, WO 02/083138, US 2004-0102360, WO 03/086404, WO 03/086279,WO 03/086394, WO 03/084473, WO 03/086403, WO 2004/041162, WO2004/096131, WO 2004/096129, WO 2004/096135, WO 2004/096130, WO2005/100356, WO 2005/100344, US 2005/029941, US 2005/44294, US2005/43361, 60/734,188, 60/652,737, 60/670,469), inhibitors of Rafkinase (for example PLX-4032), inhibitors of MEK (for example Arry-162,RO-4987655 and GSK-1120212), inhibitors of mTOR (for example AZD-8055,BEZ-235 and everolimus), and inhibitors of PI3K (for example GDC-0941,BKM-120).

As described above, the combinations with NSAID's are directed to theuse of NSAID's which are potent COX-2 inhibiting agents. For purposes ofthis specification an NSAID is potent if it possesses an IC₅₀ for theinhibition of COX-2 of 1 μM or less as measured by cell or microsomalassays.

The invention also encompasses combinations with NSAID's which areselective COX-2 inhibitors. For purposes of this specification NSAID'swhich are selective inhibitors of COX-2 are defined as those whichpossess a specificity for inhibiting COX-2 over COX-1 of at least 100fold as measured by the ratio of IC₅₀ for COX-2 over IC₅₀ for COX-1evaluated by cell or microsomal assays. Such compounds include, but arenot limited to those disclosed in U.S. Pat. No. 5,474,995, U.S. Pat. No.5,861,419, U.S. Pat. No. 6,001,843, U.S. Pat. No. 6,020,343, U.S. Pat.No. 5,409,944, U.S. Pat. No. 5,436,265, U.S. Pat. No. 5,536,752, U.S.Pat. No. 5,550,142, U.S. Pat. No. 5,604,260, U.S. Pat. No. 5,698,584,U.S. Pat. No. 5,710,140, WO 94/15932, U.S. Pat. No. 5,344,991, U.S. Pat.No. 5,134,142, U.S. Pat. No. 5,380,738, U.S. Pat. No. 5,393,790, U.S.Pat. No. 5,466,823, U.S. Pat. No. 5,633,272 and U.S. Pat. No. 5,932,598.

Inhibitors of COX-2 that may be useful in the instant method oftreatment are: 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone;and5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine; ora pharmaceutically acceptable salt thereof.

Compounds that have been described as specific inhibitors of COX-2 andtherefore may be useful in the present invention include, but are notlimited to, the following: parecoxib, BEXTRA® and CELEBREX® or apharmaceutically acceptable salt thereof.

As used above, “integrin blockers” refers to compounds which selectivelyantagonize, inhibit or counteract binding of a physiological ligand tothe α_(v)β₃ integrin, to compounds which selectively antagonize, inhibitor counteract binding of a physiological ligand to the αvβ5 integrin, tocompounds which antagonize, inhibit or counteract binding of aphysiological ligand to both the α_(v)β₃ integrin and the α_(v)β₅integrin, and to compounds which antagonize, inhibit or counteract theactivity of the particular integrin(s) expressed on capillaryendothelial cells. The term also refers to antagonists of the α_(v)β₆,α_(v)β₈, α₁β₁, α₂β₁, α₅β₁, α₆β₁ and α₆β₄ integrins. The term also refersto antagonists of any combination of α_(v)β₃, α_(v)β₅, α_(v)β₆, α_(v)β₈,α₁β₁, α₂β₁, α₅β₁, α₆β₁ and α₆β₄ integrins.

Some specific examples of tyrosine kinase inhibitors includeN-(trifluoromethylphenyl)-5-methylisoxazol-4-carboxamide,3-[(2,4-dimethylpyrrol-5-yl)methylidenyl)indolin-2-one,17-(allylamino)-17-demethoxygeldanamycin,4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxyl]quinazoline,N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine,BIBX1382,2,3,9,10,11,12-hexahydro-10-(hydroxymethyl)-10-hydroxy-9-methyl-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazocin-1-one,SH268, genistein, ST1571, CEP2563,4-(3-chlorophenylamino)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidinemethanesulfonate, 4-(3-bromo-4-hydroxyphenyl)amino-6,7-dimethoxyquinazoline,4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, SU6668, STI571A,N-4-chlorophenyl-4-(4-pyridylmethyl)-1-phthalazinamine, and EMD121974.

Combinations of the instantly claimed compounds with PPAR-γ (i.e.,PPAR-gamma) agonists and PPAR-δ (i.e., PPAR-delta) agonists may beuseful in the treatment of certain malignancies. PPAR-γ and PPAR-δ arethe nuclear peroxisome proliferator-activated receptors γ and δ. Theexpression of PPAR-γ on endothelial cells and its involvement inangiogenesis has been reported in the literature (see J. Cardiovasc.Pharmacol. 1998; 31:909-913; J. Biol. Chem. 1999; 274:9116-9121; Invest.Ophthalmol. Vis. Sci. 2000; 41:2309-2317). More recently, PPAR-γagonists have been shown to inhibit the angiogenic response to VEGF invitro; both troglitazone and rosiglitazone maleate inhibit thedevelopment of retinal neovascularization in mice. (Arch. Ophthamol.2001; 119:709-717). Examples of PPAR-γ agonists and PPAR-γ/α agonistsinclude, but are not limited to, thiazolidinediones (such as DRF2725,CS-011, troglitazone, rosiglitazone, and pioglitazone), fenofibrate,gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, JTT-501, MCC-555,GW2331, GW409544, NN2344, KRP297, NP0110, DRF4158, NN622, G1262570,PNU182716, DRF552926,2-[(5,7-dipropyl-3-trifluoromethyl-1,2-benzisoxazol-6-yl)oxy]-2-methylpropionicacid, and2(R)-7-(3-(2-chloro-4-(4-fluorophenoxy)phenoxy)propoxy)-2-ethylchromane-2-carboxylicacid.

Another embodiment of the instant invention is the use of the presentlydisclosed compounds in combination with gene therapy for the potentialtreatment of cancer. For an overview of genetic strategies to treatingcancer see Hall et al (Am. J. Hum. Genet. 61:785-789, 1997) and Kufe etal (Cancer Medicine, 5th Ed, pp 876-889, BC Decker, Hamilton 2000). Genetherapy can be used to deliver any tumor suppressing gene. Examples ofsuch genes include, but are not limited to, p53, which can be deliveredvia recombinant virus-mediated gene transfer (see U.S. Pat. No.6,069,134, for example), a uPA/uPAR antagonist (“Adenovirus-MediatedDelivery of a uPA/uPAR Antagonist Suppresses Angiogenesis-DependentTumor Growth and Dissemination in Mice,” Gene Therapy, August 1998;5(8):1105-13), and interferon gamma (J. Immunol. 2000; 164:217-222).

The compounds of the instant invention may also be administered incombination with an inhibitor of inherent multidrug resistance (MDR), inparticular MDR associated with high levels of expression of transporterproteins. Such MDR inhibitors include inhibitors of p-glycoprotein(P-gp), such as LY335979, XR9576, OC144-093, R101922, VX853 and PSC833(valspodar).

A compound of the present invention may be employed in conjunction withanti-emetic agents to treat nausea or emesis, including acute, delayed,late-phase, and anticipatory emesis, which may result from the use of acompound of the present invention, alone or with radiation therapy. Forthe prevention or treatment of emesis, a compound of the presentinvention may be used in conjunction with other anti-emetic agents,especially neurokinin-1 receptor antagonists, 5HT3 receptor antagonists,such as ondansetron, granisetron, tropisetron, and zatisetron, GABABreceptor agonists, such as baclofen, a corticosteroid such as Decadron(dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten orothers such as disclosed in U.S. Pat. Nos. 2,789,118, 2,990,401,3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712, anantidopaminergic, such as the phenothiazines (for exampleprochlorperazine, fluphenazine, thioridazine and mesoridazine),metoclopramide or dronabinol. In another embodiment, conjunctive therapywith an anti-emesis agent selected from a neurokinin-1 receptorantagonist, a 5HT3 receptor antagonist and a corticosteroid is disclosedfor the treatment or prevention of emesis that may result uponadministration of the instant compounds.

Neurokinin-1 receptor antagonists of use in conjunction with thecompounds of the present invention are fully described, for example, inU.S. Pat. Nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595,5,459,270, 5,494,926, 5,496,833, 5,637,699, 5,719,147; European PatentPublication Nos. EP 0 360 390, 0 394 989, 0 428 434, 0 429 366, 0 430771, 0 436 334, 0 443 132, 0 482 539, 0 498 069, 0 499 313, 0 512 901, 0512 902, 0 514 273, 0 514 274, 0 514 275, 0 514 276, 0 515 681, 0 517589, 0 520 555, 0 522 808, 0 528 495, 0 532 456, 0 533 280, 0 536 817, 0545 478, 0 558 156, 0 577 394, 0 585 913,0 590 152, 0 599 538, 0 610793, 0 634 402, 0 686 629, 0 693 489, 0 694 535, 0 699 655, 0 699 674, 0707 006, 0 708 101, 0 709 375, 0 709 376, 0 714 891, 0 723 959, 0 733632 and 0 776 893; PCT International Patent Publication Nos. WO90/05525, 90/05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151,92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 92/22569, 93/00330,93/00331, 93/01159, 93/01165, 93/01169, 93/01170, 93/06099, 93/09116,93/10073, 93/14084, 93/14113, 93/18023, 93/19064, 93/21155, 93/21181,93/23380, 93/24465, 94/00440, 94/01402, 94/02461, 94/02595, 94/03429,94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/08997, 94/10165,94/10167, 94/10168, 94/10170, 94/11368, 94/13639, 94/13663, 94/14767,94/15903, 94/19320, 94/19323, 94/20500, 94/26735, 94/26740, 94/29309,95/02595, 95/04040, 95/04042, 95/06645, 95/07886, 95/07908, 95/08549,95/11880, 95/14017, 95/15311, 95/16679, 95/17382, 95/18124, 95/18129,95/19344, 95/20575, 95/21819, 95/22525, 95/23798, 95/26338, 95/28418,95/30674, 95/30687, 95/33744, 96/05181, 96/05193, 96/05203, 96/06094,96/07649, 96/10562, 96/16939, 96/18643, 96/20197, 96/21661, 96/29304,96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553,97/01554, 97/03066, 97/08144, 97/14671, 97/17362, 97/18206, 97/19084,97/19942 and 97/21702; and in British Patent Publication Nos. 2 266 529,2 268 931, 2 269 170, 2 269 590, 2 271 774, 2 292 144, 2 293 168, 2 293169, and 2 302 689. The preparation of such compounds is fully describedin the aforementioned patents and publications.

In an embodiment, the neurokinin-1 receptor antagonist for use inconjunction with the compounds of the present invention is selectedfrom:2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine,or a pharmaceutically acceptable salt thereof, which is described inU.S. Pat. No. 5,719,147.

A compound of the instant invention may also be administered with anagent useful in the treatment of anemia. Such an anemia treatment agentis, for example, a continuous eythropoiesis receptor activator (such asepoetin alfa).

A compound of the instant invention may also be administered with anagent useful in the treatment of neutropenia. Such a neutropeniatreatment agent is, for example, a hematopoietic growth factor whichregulates the production and function of neutrophils such as a humangranulocyte colony stimulating factor, (G-CSF). Examples of a G-CSFinclude filgrastim.

A compound of the instant invention may also be administered with animmunologic-enhancing drug, such as levamisole, isoprinosine andZadaxin.

A compound of the instant invention may also be useful for treating orpreventing cancer in combination with P450 inhibitors including:xenobiotics, quinidine, tyramine, ketoconazole, testosterone, quinine,methyrapone, caffeine, phenelzine, doxorubicin, troleandomycin,cyclobenzaprine, erythromycin, cocaine, furafyline, cimetidine,dextromethorphan, ritonavir, indinavir, amprenavir, diltiazem,terfenadine, verapamil, cortisol, itraconazole, mibefradil, nefazodoneand nelfinavir.

A compound of the instant invention may also be useful for treating orpreventing cancer in combination with Pgp and/or BCRP inhibitorsincluding: cyclosporin A, PSC833, GF120918, cremophorEL, fumitremorginC, Ko132, Ko134, Iressa, Imatnib mesylate, EKI-785, CII 033, novobiocin,diethylstilbestrol, tamoxifen, resperpine, VX-710, tryprostatin A,flavonoids, ritonavir, saquinavir, nelfinavir, omeprazole, quinidine,verapamil, terfenadine, ketoconazole, nifidepine, FK506, amiodarone,XR9576, indinavir, amprenavir, cortisol, testosterone, LY335979,OC144-093, erythromycin, vincristine, digoxin and talinolol.

A compound of the instant invention may also be useful for treating orpreventing cancer, including bone cancer, in combination withbisphosphonates (understood to include bisphosphonates, diphosphonates,bisphosphonic acids and diphosphonic acids). Examples of bisphosphonatesinclude but are not limited to: etidronate (Didronel), pamidronate(Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate(Zometa), ibandronate (Boniva), incadronate or cimadronate, clodronate,EB-1053, minodronate, neridronate, piridronate and tiludronate includingany and all pharmaceutically acceptable salts, derivatives, hydrates andmixtures thereof.

A compound of the instant invention may also be useful for treating orpreventing breast cancer in combination with aromatase inhibitors.Examples of aromatase inhibitors include but are not limited to:anastrozole, letrozole and exemestane.

A compound of the instant invention may also be useful for treating orpreventing cancer in combination with siRNA therapeutics.

The compounds of the instant invention may also be administered incombination with γ-secretase inhibitors and/or inhibitors of NOTCHsignaling. Such inhibitors include compounds described in WO 01/90084,WO 02/30912, WO 01/70677, WO 03/013506, WO 02/36555, WO 03/093252, WO03/093264, WO 03/093251, WO 03/093253, WO 2004/039800, WO 2004/039370,WO 2005/030731, WO 2005/014553, U.S. Ser. No. 10/957,251, WO2004/089911, WO 02/081435, WO 02/081433, WO 03/018543, WO 2004/031137,WO 2004/031139, WO 2004/031138, WO 2004/101538, WO 2004/101539 and WO02/47671 (including LY-450139).

Inhibitors of Akt, as disclosed in the following publications; WO02/083064, WO 02/083139, WO 02/083140, US 2004-0116432, WO 02/083138, US2004-0102360, WO 03/086404, WO 03/086279, WO 03/086394, WO 03/084473, WO03/086403, WO 2004/041162, WO 2004/096131, WO 2004/096129, WO2004/096135, WO 2004/096130, WO 2005/100356, WO 2005/100344, US2005/029941, US 2005/44294, US 2005/43361, 60/734,188, 60/652,737,60/670,469, and including compounds of the instant invention, may alsobe useful in combination with potassium salts, magnesium salts,beta-blockers (such as atenolol) and endothelin-a (ETa)antagonists withthe goal of maintaining cardiovascular homeostasis.

Inhibitors of Akt, as disclosed in the following publications; WO02/083064, WO 02/083139, WO 02/083140, US 2004-0116432, WO 02/083138, US2004-0102360, WO 03/086404, WO 03/086279, WO 03/086394, WO 03/084473, WO03/086403, WO 2004/041162, WO 2004/096131, WO 2004/096129, WO2004/096135, WO 2004/096130, WO 2005/100356, WO 2005/100344, US2005/029941, US 2005/44294, US 2005/43361, 60/734,188, 60/652,737,60/670,469, and including compounds of the instant invention, may alsobe useful in combination with insulin, insulin secretagogues, PPAR-gammaagonists, metformin, somatostatin receptor agonists such as octreotide,DPP4 inhibitors, sulfonylureas and alpha-glucosidase inhibitors with thegoal of maintaining glucose homeostasis.

A compound of the instant invention may also be useful for treating orpreventing cancer in combination with PARP inhibitors: olaparib, MK-4827and veliparib.

A compound of the instant invention may also be useful for treatingcancer in combination with the following chemotherapeutic agents:abarelix (Plenaxis Depot®); aldesleukin (Prokine®); Aldesleukin(Proleukin®); Alemtuzumabb (Campath®); alitretinoin (Panretin®);allopurinol (Zyloprim®); altretamine (Hexylen®); amifostine (Ethyol®);anastrozole (Arimidex®); arsenic trioxide (Trisenox®); asparaginase(Elspar®); azacitidine (Vidaza®); bendamustine hydrochloride (Treanda®);bevacuzimab (Avastin®); bexarotene capsules (Targretin®); bexarotene gel(Targretin®); bleomycin (Blenoxane®); bortezomib (Velcade®); brefeldinA; busulfan intravenous (Busulfex®); busulfan oral (Myleran®);calusterone (Methosarb®); capecitabine (Xeloda®); carboplatin(Paraplatin®); carmustine (BCNU®, BiCNU®); carmustine (Gliadel®);carmustine with Polifeprosan 20 Implant (Gliadel Wafer®); celecoxib(Celebrex®); cetuximab (Erbitux®); chlorambucil (Leukeran®); cisplatin(Platinol®); cladribine (Leustatin®, 2-CdA®); clofarabine (Clolar®);cyclophosphamide (Cytoxan®, Neosar®); cyclophosphamide (CytoxanInjection®); cyclophosphamide (Cytoxan Tablet®); cytarabine(Cytosar-U®); cytarabine liposomal (DepoCyt®); dacarbazine (DTIC-Dome®);dactinomycin, actinomycin D (Cosmegen®); dalteparin sodium injection(Fragmin®); Darbepoetin alfa (Aranesp®); dasatinib (Sprycel®);daunorubicin liposomal (DanuoXome®); daunorubicin, daunomycin(Daunorubicin®); daunorubicin, daunomycin (Cerubidine®); degarelix(Firmagon®); Denileukin diftitox (Ontak®); dexrazoxane (Zinecard®);dexrazoxane hydrochloride (Totect®); didemnin B; 17-DMAG; docetaxel(Taxotere®); doxorubicin (Adriamycin PFS®); doxorubicin (Adriamycin®,Rubex®); doxorubicin (Adriamycin PFS Injection®); doxorubicin liposomal(Doxil®); dromostanolone propionate (Dromostanolone®); dromostanolonepropionate (Masterone Injection®); eculizumab injection (Soliris®);Elliott's B Solution (Elliott's B Solution®); eltrombopag (Promacta®);epirubicin (Ellence®); Epoetin alfa (Epogen®); erlotinib (Tarceva®);estramustine (Emcyt®); ethinyl estradiol; etoposide phosphate(Etopophos®); etoposide, VP-16 (Vepesid®); everolimus tablets(Afinitor®); exemestane (Aromasin®); ferumoxytol (Feraheme Injection®);Filgrastim (Neupogen®); floxuridine (intraarterial) (FUDR®); fludarabine(Fludara®); fluorouracil, 5-FU (Adrucil®); fulvestrant (Faslodex®);gefitinib (Iressa®); geldanamycin; gemcitabine (Gemzar®); gemtuzumabozogamicin (Mylotarg®); goserelin acetate (Zoladex Implant®); goserelinacetate (Zoladex®); histrelin acetate (Histrelin Implant®); hydroxyurea(Hydrea®); Ibritumomab Tiuxetan (Zevalin®); idarubicin (Idamycin®);ifosfamide (IFEX®); imatinib mesylate (Gleevec®); interferon alfa 2a(Roferon A®); Interferon alfa-2b (Intron A®); iobenguane 1123 injection(AdreView®); irinotecan (Camptosar®); ixabepilone (Ixempra®); lapatinibtablets (Tykerb®); lenalidomide (Revlimid®); letrozole (Femara®);leucovorin (Wellcovorin®, Leucovorin®); Leuprolide Acetate (Eligard®);levamisole (Ergamisol®); lomustine, CCNU (CeeBU®); meclorethamine,nitrogen mustard (Mustargen®); megestrol acetate (Megace®); melphalan,L-PAM (Alkeran®); mercaptopurine, 6-MP (Purinethol®); mesna (Mesnex®);mesna (Mesnex Tabs®); methotrexate (Methotrexate®); methoxsalen(Uvadex®); 8-methoxypsoralen; mitomycin C (Mutamycin®); mitotane(Lysodren®); mitoxantrone (Novantrone®); mitramycin; nandrolonephenpropionate (Durabolin-50®); nelarabine (Arranon®); nilotinib(Tasigna®); Nofetumomab (Verluma®); ofatumumab (Arzerra®); Oprelvekin(Neumega®); oxaliplatin (Eloxatin®); paclitaxel (Paxene®); paclitaxel(Taxol®); paclitaxel protein-bound particles (Abraxane®); palifermin(Kepivance®); pamidronate (Aredia®); panitumumab (Vectibix®); pazopanibtablets (Votrienttm®); pegademase (Adagen (Pegademase Bovine)®);pegaspargase (Oncaspar®); Pegfilgrastim (Neulasta®); pemetrexed disodium(Alimta®); pentostatin (Nipent®); pipobroman (Vercyte®); plerixafor(Mozobil®); plicamycin, mithramycin (Mithracin®); porfimer sodium(Photofrin®); pralatrexate injection (Folotyn®); procarbazine(Matulane®); quinacrine (Atabrine®); rapamycin; Rasburicase (Elitek®);raloxifene hydrochloride (Evista®); Rituximab (Rituxan®); romidepsin(Istodax®); romiplostim (Nplate®); sargramostim (Leukine®); Sargramostim(Prokine®); sorafenib (Nexavar®); streptozocin (Zanosar®); sunitinibmaleate (Sutent®); talc (Sclerosol®); tamoxifen (Nolvadex®);temozolomide (Temodar®); temsirolimus (Torisel®); teniposide, VM-26(Vumon®); testolactone (Teslac®); thioguanine, 6-TG (Thioguanine®);thiopurine; thiotepa (Thioplex®); topotecan (Hycamtin®); toremifene(Fareston®); Tositumomab (Bexxar®); Tositumomab/I-131 tositumomab(Bexxar®); trans-retinoic acid; Trastuzumab (Herceptin®); tretinoin,ATRA (Vesanoid®); triethylenemelamine; Uracil Mustard (Uracil MustardCapsules®); valrubicin (Valstar®); vinblastine (Velban®); vincristine(Oncovin®); vinorelbine (Navelbine®); vorinostat (Zolinza®); wortmannin;and zoledronate (Zometa®).

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR), e.g., 1996edition (Medical Economics Company, Montvale, N.J. 07645-1742, USA), thePhysician's Desk Reference, 56^(th) Edition, 2002 (published by MedicalEconomics company, Inc. Montvale, N.J. 07645-1742), and the Physician'sDesk Reference, 57^(th) Edition, 2003 (published by Thompson PDR,Montvale, N.J. 07645-1742).

The invention disclosed herein is exemplified by the followingpreparations and examples which should not be construed to limit thescope of the disclosure.

EXAMPLES Example 1 Methods of Preparing the Compounds of Formula (I)

The compounds of this invention may be made by a variety of methods,including standard chemistry. Any previously defined variable willcontinue to have the previously defined meaning unless otherwiseindicated. Illustrative general synthetic methods are set out below, andthen specific compounds of the Formula (I) are prepared in the Examples.

Compounds of general Formula (I) may be prepared by methods known in theart of organic synthesis as set forth in part by the following synthesisschemes. In all of the schemes described below, it is well understoodthat protecting groups for sensitive or reactive groups are employedwhere necessary in accordance with general principles of chemistry.Protecting groups are manipulated according to standard methods oforganic synthesis (T. W. Green and P. G. M. Wuts (1991) ProtectingGroups in Organic Synthesis, John Wiley & Sons). These groups areremoved at a convenient stage of the compound synthesis using methodsthat are readily apparent to those skilled in the art. The selection ofprotecting groups as well as the reaction conditions and order ofreaction steps shall be consistent with the preparation of compounds ofFormula (I). Those skilled in the art will recognize whether astereocenter exists in compounds of Formula (I). Accordingly, thepresent invention includes all possible stereoisomers and includes notonly mixtures of stereoisomers (such as racemic compounds) but theindividual stereoisomers as well. When a compound is desired as a singleenantiomer, it may be obtained by stereospecific synthesis or byresolution of the final product or any convenient intermediate.Resolution of the final product, an intermediate, or a starting materialmay be effected by any suitable method known in the art. See, forexample, Stereochemistry of Organic Compounds by E. L. Eliel, S. H.Wilen, and L. N. Mander (Wiley-Interscience, 1994).

The following solvents, reagents, protecting groups, moieties, and otherdesignations may be referred to by their abbreviations:

Me=methyl; Et=ethyl; Pr=propyl; iPr=isopropyl, Bu=butyl;t-Bu=tert-butyl; Ph=phenyl, and Ac=acetyl

μl=microliters

AcOH or HOAc=acetic acid

ACN=acetonitrile

Ad=adamantyl

APCl or APC=atmospheric-pressure chemical ionization

aq=aqueous

BINAP=2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene

Bn=benzyl

Boc or BOC=tert-butoxycarbonyl

Bz=benzoyl

Cbz=benyzloxycarbonyl

CDI=1,1′-Carbonyldiimidazole

DAST=diethylaminosulfur trifluoride

dba=dibenzylideneacetone

DBU=1,8-Diaza-7-bicyclo[5.4.0]undecene

DCM=dichloromethane

DMAP=4-Dimethylaminopyridine

DIBAL or DIBALH=diisobutylaluminum hydride

DIEA or Hünig's Base=N,N-diisopropylethylamine

DMA=N,N-dimethylacetamide

DMF=dimethylformamide

DMSO=dimethyl sulfoxide

dppf=1,1′-Bis(diphenylphosphino)ferrocene

DMT=Dimercaptotriazine

DTT=dithiothreitol

EDC=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

EDTA=ethylenediamine tetraacetic acid

ESI or ES=Electrospray ionization

EtOAc=ethyl acetate

g=grams

GST=glutathione S-transferase

h=hour

HMDS=1,1,1,3,3,3-hexamethyldisilazane

HATU=N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate

HPLC=high-performance liquid chromatography

HOBt=1-hydroxybenzotriazole

LAH=lithium aluminium hydride

LDA=lithium diisopropylamide

LC=liquid chromatography

LCMS=liquid chromatography mass spectrometry

min=minute

mg=milligrams

mL=milliliters

mmol=millimoles

mCPBA=meta-Chloroperoxybenzoic acid

Me=methyl

MeOH=methanol

MS=mass spectrometry

MTBE=methyl tert-butyl ether

NBS=N-bromosuccinimide

NMP=N-methylpyrrolidone

NMR=nuclear magnetic resonance spectroscopy

PTLC=preparative thin layer chromatography

rac=racemic mixture

R_(f)=retardation factor

RT or rt=room temperature (ambient, about 25° C.)

sat=saturated

SFC=supercritical fluid chromatography

TBAF=tetrabutylammonium fluoride

TBSCl=t-butyldimethylsilyl chloride

TBS=t-butyldimethylsilyl

TEA=triethylamine (Et₃N)

TFA=trifluoroacetic acid

TFAA=trifluoroacetic anhydride

THF=tetrahydrofuran

TLC=thin layer chromatography

TMS=trimethylsilyl

Tris=tris(hydroxymethyl)aminomethane

Xantphos=4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

Preparative Example 1.1(R)-6-chloro-N-(1-cyclobutylethyl)-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridin-4-amine

Step 1: 1-(Bromomethyl)-4-(trifluoromethyl)benzene (6.36 g, 26.6 mmol)was added to a stirred solution of4,6-dichloro-3H-imidazo[4,5-c]pyridine (5.0 g, 26.6 mmol) and cesiumcarbonate (10.40 g, 31.9 mmol) in DMA (30.0 ml) at room temperature andwas stirred for 2 h. Water was added, and the solids were filtered anddried overnight. Crude ¹H NMR showed ˜4:1 ratio of undesired4,6-dichloro-1-(4-(trifluoromethyl)benzyl)-1H-imidazo[4,5-c]pyridine:desired4,6-dichloro-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine.The crude residue was purified by silica gel chromatography (EtOAc/DCM,0% to 20%) to afford the desired4,6-dichloro-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine(fraction 1) and the undesired4,6-dichloro-1-(4-(trifluoromethyl)benzyl)-1H-imidazo[4,5-c]pyridine(fraction 2).4,6-dichloro-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine: MSESI calc'd for C₁₄H₈Cl₂F₃N₃ [M+H]⁺ 346, found 346.

Step 2: Potassium fluoride (0.940 g, 16.18 mmol) was added to a stirredsolution of4,6-dichloro-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine(2.8 g, 8.09 mmol) in DMA (22.40 ml). The solution was stirred at roomtemperature for 5 min. (R)-1-cyclobutylethanamine hydrochloride (2.194g, 16.18 mmol) and DBU (3.66 ml, 24.27 mmol) were added and the reactionmixture was heated at 120° C. overnight. The reaction mixture was cooledto room temperature and diluted with water and EtOAc. The aqueous layerwas extracted with EtOAc (2×). The organic layers were combined, driedand concentrated. The residue was purified by silica gel chromatography(0-100% ethyl acetate/hexanes, linear gradient) to afford(R)-6-chloro-N-(1-cyclobutylethyl)-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridin-4-amine.MS ESI calc'd for C₂₀H₂₀ClF₃N₄ [M+H]⁺ 409, found 409.

Preparative Example 1.2 (R)-1-cyclobutylethanamine hydrochloride

Step 1: Into a 20-L 4-necked round-bottom flask was placed a solution ofcyclobutylmethanol (1000 g, 11.61 mol) in dichloromethane (10 L). Thiswas followed by the addition of Dess-Martin periodinane (4683 g, 11.04mol) in several batches at 10-15° C. over 120 min. The resultingsolution was stirred for 2 h at room temperature and then quenched bythe addition of 20 L of cold, saturated aqueous sodium bicarbonatesolution. Solids were removed by filtration and washed with 5 L ofdichloromethane. The filtrate was extracted with dichloromethane. Theorganic layers were combined, dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with DCM:PE (2:1). This resulted in 100 L ofcyclobutanecarbaldehyde in dichloromethane and petroleum ether solution.Step 2: Into a 50-L barrel was placed cyclobutanecarbaldehyde indichloromethane and petroleum ether (33 L of the solution described atthe end of Step 1), (S)-2-methylpropane-2-sulfinamide (500 g, 4.13 mol)and copper sulfate (2 kg, 13.33 mol). The resulting solution was stirredfor 2 days at room temperature. Solids were removed by filtration. Thefiltrate was concentrated under vacuum. The residue was applied onto asilica gel column and eluted with ethyl acetate/petroleum ether (1:5) toafford (S)—N-[(1E)-cyclobutylmethylidene]-2-methylpropane-2-sulfinamide.

Step 3: Into a 10-L 4-neck round-bottom flask purged and maintained withan inert atmosphere of nitrogen was placed a solution of(S)—N-[(1E)-cyclobutylmethylidene]-2-methylpropane-2-sulfinamide (200 g,1.07 mol) in tetrahydrofuran (3000 mL). This was followed by theaddition of methylmagnesium bromide in ether (1070 mL, 3.00 equiv)dropwise with stirring at −78° C. over 1 hr. The resulting solution wasstirred for 1 h at −70° C., 1 h at −60° C., 1 h at −50° C. and 2 h at−40° C. The reaction was then quenched by the addition of 10 L ofsaturated aqueous NH₄Cl solution. The resulting solution was extractedwith 2×3 L of ether. The organic layers were combined, washed with 2×3 Lof brine, dried over anhydrous sodium sulfate, and concentrated undervacuum. The residue was diluted with 250 mL of n-hexane. The resultingsolid was collected and washed with 2×100 mL of cold n-hexane to afford(S)—N-[(1R)-1-cyclobutylethyl]-2-methylpropane-2-sulfinamide.

Step 4: Into a 10-L 4-neck round-bottom flask was placed a solution of(S)—N-[(1R)-1-cyclobutylethyl]-2-methylpropane-2-sulfinamide (400 g,1.97 mol) in methanol (2800 mL). This was followed by the addition ofHCl/p-dioxane (5M, 1.6 L) dropwise with stirring at 0° C. over 60 min.The resulting solution was stirred for 60 min at room temperature. Thesolution was then concentrated under vacuum. The residue was dilutedwith 4 L of n-hexane and stirred for 30 min at room temperature. Thesolid was collected by filtration. The filtrate was diluted with 1200 mLof CH₃CN and stirred for 30 min at room temperature. The solid wascollected by filtration. The combined solids were dried in an oven underreduced pressureto afford (1R)-1-cyclobutylethan-1-amine as a hydrogenchloride salt. MS ESI calc'd for C₆H₁₃N [M+H]⁺ 100, found 100. ¹H NMR(400 MHz, DMSO-d₆): δ 7.95 (s, 3H), 3.11 (s, 1H), 2.32-2.42 (m, 1H),1.75-2.01 (m, 6H), 1.10 (s, 3H).

Example 1.1(R)-4-(1-cyclobutylethypamino)-2-(4-isopropylpyridin-2-yl)-7-methyl-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine-6-carboxylicacid

Step 1: A vial containing2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (67.6 mg, 0.142mmol) and allylpalladium(II) chloride dimer (26 mg, 0.071 mmol) in DMA(400 ul) was evacuated and refilled with Ar (3×). The resulting solutionwas warmed to 70° C. for 20 minutes. In a separate vial was added zinccyanide (92 mg, 0.78 mmol),(R)-6-chloro-N-(1-cyclobutylethyl)-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridin-4-amine(290 mg, 0.71 mmol) and DMA (500 uL). The mixture was degassed with Arfor 15 minutes, and the catalyst solution was added to the mixture. Theresulting mixture was stirred at 120° C. overnight. The mixture wascooled to room temperature and concentrated. The residue was dissolvedin DCM purified by silica gel chromatography (0-100% ethylacetate/hexanes, linear gradient) to give(R)-4-((1-cyclobutylethyl)amino)-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ESI calc'd for C₂₁H₂₀F₃N₅ [M+H]⁺ 400, found 400.

Step 2: NBS (73.5 mg, 0.413 mmol) was added to a stirred, roomtemperature mixture of(R)-4-((1-cyclobutylethyl)amino)-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile(150 mg, 0.376 mmol) in degassed chloroform (3 ml) in a sealed tube. Themixture was heated to 45° C. and stirred under Ar for 1 hour. Themixture was cooled to room temperature and diluted with DCM. The mixturewas then transferred to a separatory funnel, washed with saturatedsodium bicarbonate, dried over sodium sulfate, filtered, andconcentrated in vacuo. The resulting dark orange oil was purified bysilica gel chromatography (0-100% ethyl acetate/hexanes, lineargradient) to afford(R)-7-bromo-4-((1-cyclobutylethyl)amino)-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ESI calc'd for C₂₁H₁₉BrF₃N₅ [M+H]⁺ 479, found 479.

Step 3: To a vial containing(R)-7-bromo-4-((1-cyclobutylethyl)amino)-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile(65 mg, 0.14 mmol), methylboronic acid (16.3 mg, 0.3 mmol),1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride-chloroformadduct (11.1 mg, 0.014 mmol) and potassium phosphate (87 mg, 0.41 mmol)was added 1,4-dioxane (800 ul) and water (200 uL). The vial wasevacuated and refilled with Ar (3×). The solution was heated to 120° C.for 10 minutes under microwave irradiation. The mixture was cooled toroom temperature and quenched with saturated sodium bicarbonate andethyl acetate. The organic layer was collected and concentrated. Theresidue was dissolved in DCM and purified by silica gel chromatography(0-100% ethyl acetate/hexanes, linear gradient) to give(R)-4-((1-cyclobutylethyl)amino)-7-methyl-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ESI calc'd for C₂₂H₂₂F₃N₅ [M+H]⁺ 414, found 414.

Step 4: To a vial containing palladium(II) acetate (4.3 mg, 0.019 mmol)and butyldi-1-adamantylphosphine (13.9 mg, 0.039 mmol) was added1,4-dioxane (300 ul). The vial was evacuated and refilled with Ar (3×).The solution was warmed to 70° C. for 20 minutes. In a separate vialwere combined pivalic acid (9.9 mg, 0.097 mmol), cesium fluoride (44 mg,0.29 mmol), 2-bromo-4-isopropylpyridine (purchased from CombiPhosCatalysts, Inc.) (29 mg, 0.15 mmol),(R)-4-((1-cyclobutylethyl)amino)-7-methyl-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile(40 mg, 0.097 mmol) and 1,4-dioxane (0.5 mL). The mixture was degassedwith Ar for 15 minutes, and the catalyst solution was added to themixture. The resulting mixture was stirred at 130° C. for 3 days. Themixture was cooled to room temperature and concentrated. The residue wasdissolved in DCM and purified by silica gel chromatography (0-100% ethylacetate/hexanes, linear gradient) to give(R)-4-(1-cyclobutylethypamino)-2-(4-isopropylpyridin-2-yl)-7-methyl-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ESI calc'd for C₃₀H₃₁F₃N₆ [M+H]⁺ 533, found 533.

Step 5: To(R)-4-((1-cyclobutylethyl)amino)-2-(4-isopropylpyridin-2-yl)-7-methyl-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile(26 mg, 0.049 mmol) dissolved in ethanol (1 ml) was added sodiumhydroxide (5.0 M in water, 1 mL, 5.0 mmol). The reaction was heated to110° C. and stirred overnight. The solution was cooled to roomtemperature, concentrated, and then diluted with EtOAc. It was washedwith 1N HCl, then dried over sodium sulfate, filtered and concentrated.The residue was purified by mass triggered, reverse phase (C-18)preparative HPLC (acetonitrile:water: 0.1% v/v trifluoroacetic acidmodifier) to afford (R)-4-((1-cyclobutylethyl)amino)-2-(4-isopropylpyridin-2-yl)-7-methyl-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine-6-carboxylicacid (as a TFA salt). MS ESI calc'd for C₃₀H₃₂F₃N₅O₂ [M+H]⁺ 552, found552. ¹H NMR (500 MHz, CDCl₃): δ 0.99 (d, J=6.1 Hz, 3H); 1.32-1.25 (m,1H); 1.35 (d, J=6.9 Hz, 6H); 1.50-1.42 (m, 1H); 1.63-1.54 (m, 2H);1.78-1.67 (m, 1H); 1.92-1.85 (m, 1H); 2.06-1.99 (m, 1H); 2.89 (s, 3H);3.08-3.02 (m, 1H); 3.81 (s, 1H); 5.30 (s, 1H); 6.36 (d, J=17.1 Hz, 1H);6.59 (d, J=16.8 Hz, 1H); 7.29-7.27 (m, 1H); 7.33 (d, J=8.0 Hz, 2H); 7.68(d, J=8.0 Hz, 2H); 8.33 (s, 1H); 8.45 (d, J=5.0 Hz, 1H).

Example 1.2, Example 1.3 and Example 1.4 in Table 1 were prepared usingprocedures which are analogous to those described above in Example 1.1(Step 1, Step 4 and Step 5). Example 1.2 and Example 1.3 were preparedfrom(R)-6-chloro-N-(1-cyclobutylethyl)-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridin-4-amine(Preparative Example 1.1). Example 1.4 was prepared from4,6-dichloro-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine(Preparative Example 2.3).

TABLE 1 FRET IC₅₀ Salt [M + H]⁺ [M + H]⁺ Ex. (nM) Structure ChemicalName Form Calc'd Obsv'd 1.1  60

(R)-4-((1- cyclobutylethyl)amino)-2- (4-isopropylpyridin-2-yl)-7-methyl-3-(4- (trifluoromethyl)benzyl)- 3H-imidazo[4,5-c]pyridine-6-carboxylic acid TFA 552 552 1.2  29

4-{[(1R)-1- cyclobutylethyl]amino}-2- [4-(1-methylethyl)pyridin-2-yl]-3-[4- (trifluoromethyl)benzyl]-3H- imidazo[4,5-c]pyridine-6-carboxylic acid TFA 538 538 1.3 122

4-{[(1R)-1- cyclobutylethyl]amino}-2- (3-methylphenyl)-3-[4-(trifluoromethyl)benzyl]-3H- imidazo[4,5-c]pyridine-6- carboxylic acidTFA 509 509 1.4  4

4-{[(1R)-1- cyclobutylethyl]amino}-3- [(trans-4-methylcyclohexyl)methyl]- 2-[4-(1-methylethyl)pyridin-2-yl]-3H-imidazo[4,5- c]pyridine-6-carboxylic acid TFA 490 490

Preparative Example 2.1 Trans-4-methylcyclohexanecarbaldehyde

Step 1: To a solution of trans-dimethyl cyclohexane-1,4-dicarboxylate(1000 g, 5 mol) in THF (3000 mL) cooled to −20° C. was added LiAlH₄ (570g, 15 mol). The mixture was stirred at room temperature for 3 h,quenched with water (10 L), and filtered. The filtrate was concentratedin vacuo to give trans-cyclohexane-1,4-diyldimethanol as white solid. ¹HNMR (CDCl₃, 400 MHz): δ 3.48-3.46 (m, 4H), 1.86-1.84 (m, 4H), 1.47-1.42(m, 4H), 1.01-0.96 (m, 4H).

Step 2: 4-Toluenesulfonyl chloride (742.5 g, 3.75 mol) was added to asolution of trans-cyclohexane-1,4-diyldimethanol (500 g, 4.17 mol) andEt₃N (695 g, 5 mol) in DCM (6000 mL) at −20° C. The mixture was stirredat room temperature for 10 h and then quenched with water (10 L). Theorganic layer was separated, the aqueous layer was extracted with DCM(2×3 L), and the combined organic layer was dried over sodium sulfate,filtered, and concentrated in vacuo to givetrans-4-(hydroxymethyl)cyclohexylmethyl 4-methylbenzenesulfonate as ayellow oil.

Step 3: LiAlH₄ (153 g, 4 mol) was added to a solution oftrans-4-(hydroxymethyl)cyclohexylmethyl 4-methylbenzenesulfonate (400 g,1.34 mol) in THF (3000 mL) at −20° C. The mixture was stirred at roomtemperature for 3 h. It was quenched with water (10 L) and filtered. Thefiltrate was concentrated in vacuo to givetrans-(4-methylcyclohexyl)methanol.

Step 4: To a solution of trans-(4-methylcyclohexyl)methanol (160 g, 1.25mol) in DCM (1500 mL) was added pyridinium chlorochromate (405 g, 1.88mol) at 0° C., and the mixture was stirred at room temperature for 2 h.It was filtered and the filtrate was concentrated in vacuo to givetrans-4-methylcyclohexanecarbaldehyde.

Preparative Example 2.2 tert-butyl(3-amino-2,6-dichloropyridin-4-yl)carbamate

Step 1: A solution of 2,6-dichloropyridin-4-amine (500 g, 3.08 mol) insulfuric acid (5 L) was cooled to 0° C. Nitric acid (2 L, 15 mol) wasslowly added dropwise to the above resulting solution. The starting2,6-dichloropyridin-4-amine was consumed after 3 hr. The reactionmixture was added to water (20 L), and the solid was filtered to giveN-(2,6-dichloropyridin-4-yl)nitramide. This material was used directlyin the next step. ¹H NMR (CDCl₃, 400 MHz): δ 7.11-7.14 (m, 1H),7.09-7.09 (s, 1H).

Step 2: N-(2,6-dichloropyridin-4-yl)nitramide (610 g, 10.8 mol) insulfuric acid (5 L) was heated to 100° C. and stirred for 3 h. Theresulting mixture was slowly added to ice water (20 L). The solid wasfiltered to give crude 2,6-dichloro-3-nitropyridin-4-amine. ¹H NMR(CDCl₃ 400 MHz): δ 6.95 (s, 1H), 5.78 (s, 2H).

Step 3: To a solution of 2,6-dichloro-3-nitropyridin-4-amine (580 g, 2.8mol) and di-tert-butyl dicarbonate (2431 g, 11.2 mol) in THF (3000 mL)cooled to −20° C. was added LiHMDS (1 M in THF, 11.2 L, 11.2 mol). Themixture was stirred at room temperature for 3 h. It was quenched withammonium chloride (6 L) and extracted with EtOAc (2×2 L). The organiclayer was washed with saturated sodium bicarbonate (1 L) and brine,dried with anhydrous sodium sulfate, and concentrated in vacuo to givecrude tert-butyl (2,6-dichloro-3-nitropyridin-4-yl)carbamate.

Step 4: A mixture of tert-butyl(2,6-dichloro-3-nitropyridin-4-yl)carbamate (700 g, 2.27 mol) and iron(1272.7 g, 22.7 mol) in ethanol (5 L) and water (1 L) was stirred atroom temperature for 10 h. The mixture was filtered, the filtrate wasconcentrated in vacuo, and the crude product was crystallized usingEtOAc to give tert-butyl (3-amino-2,6-dichloropyridin-4-yl)carbamate.

Preparative Example 2.34,6-dichloro-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine

Step 1: To a solution of tert-butyl(3-amino-2,6-dichloropyridin-4-yl)carbamate (353 g, 1.27 mol) andtrans-4-methylcyclohexanecarbaldehyde (160 g, 1.27 mol) in DCM (8.0 L)and acetic acid (2 ml) was added sodium triacetoxyborohydride (807.7 g,3.81 mol) at 0° C. The mixture was stirred for 15 min, and then warmedto room temperature. The mixture was stirred for 15 h at roomtemperature and then quenched with water (10 L). The mixture wasfiltered, the filtrate was separated, and the organic layer wasconcentrated under reduced pressure to give crude product. The crudeproduct was purified over a silica gel column, eluting with EtOAc:petroleum ether (0-1:10), to give tert-butyl(2,6-dichloro-3-(((trans-4-methylcyclohexyl)methyl)amino)pyridin-4-yl)carbamate.

Step 2: A solution of tert-butyl(2,6-dichloro-3-(((trans-4-methylcyclohexyl)methyl)amino)pyridin-4-yl)carbamate(150 g, 0.386 mol) in HCl/1,4-dioxane (4 M, 3.0 L) was stirred at 45° C.for 15 h. The mixture was concentrated under reduced pressure to givecrude2,6-dichloro-N³-((trans-4-methylcyclohexyl)methyl)pyridine-3,4-diamine.

Step 3: A solution of2,6-dichloro-N³-((trans-4-methylcyclohexyl)methyl)pyridine-3,4-diamine(126 g, 0.386 mol) in triethylorthoformate (1.0 L) and acetic anhydride(1.0 L) was stirred at 90° C. for 3 h. The solution was concentrated invacuo, and the residue was dissolved in DCM/10% NaOH (2.0 L/1.0 L). Theorganic layer was separated and concentrated. The crude product waspurified by a silica gel column, eluting with DCM/petroleum ether (1:1),to give4,6-dichloro-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine.MS ESI calc'd. for C₁₄H₁₇Cl₂N₃ [M+H]⁺ 298, found 298. ¹H NMR (400 MHz,CDCl₃): 7.96 (s, 1H); 7.66 (m, 1H); 4.28-4.26 (d, 2H); 1.85-1.79 (m,1H); 1.73-1.71 (d, 2H), 1.70-1.61 (d, 2H), 1.34-1.33 (m, 1H) 1.12-1.02(m, 2 H), 0.94-0.84 (m, 5H).

Example 2.13-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one

Step 1: N-bromosuccinimide (3.28 g, 18.4 mmol) was added to a solutionof4,6-dichloro-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine(Preparative Example 2.3, 5 g, 16.8 mmol) stirring in degassedchloroform (168 mL) at room temperature. The reaction was heated toreflux for 1 hour. The mixture was cooled to room temperature, dilutedwith dichloromethane, and washed with saturated aqueous sodiumthiosulfate (2×) and brine. The organic layer was dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel chromatography (0-100% ethyl acetate/hexanes,linear gradient) to afford2-bromo-4,6-dichloro-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine.MS ESI calc'd. for C₁₄H₁₆BrCl₂N₃ [M+H]⁺ 378, found 378.

Alternatively, Step 1 could be performed as follows:

4,6-dichloro-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine(1 g, 3.35 mmol) was dissolved in THF (10 mL). Disodium hydrogenphosphate (1.43 g, 10.1 mmol) was added, and the reaction was warmed to35° C. with stirring. 1,3-dibromo-5,5-dimethylhydantoin (1.15 g, 4.02mmol) was added in 1 portion, and the reaction was continued withstirring at 35° C. After 45 minutes, the reaction was diluted with EtOAc(100 mL) and washed with aqueous NaHSO₃ and brine. The organic layer wasdried over Na₂SO₄, filtered, and concentrated. Purification of theresidue on a silica gel column with 0 to 50% EtOAc/hexanes provided2-bromo-4,6-dichloro-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine.

Step 2: To a vial were added2-bromo-4,6-dichloro-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine(3.13 g, 8.30 mmol), (R)-3-phenylmorpholine (purchased from BeyondPharmatech) (2.71 g, 16.6 mmol), potassium fluoride (2.41 g, 41.5 mmol),DMSO (25.5 mL), and N,N-diisopropylethylamine (7.25 mL, 41.5 mmol). Thevial was sealed and heated to 100° C. for 16 hours. The reaction mixturewas cooled to room temperature, diluted with ethyl acetate, and washedwith water and then brine. The organic layer was dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel chromatography (0-60% ethyl acetate/hexanes,linear gradient) to afford4,6-dichloro-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine.MS ESI calc'd. for C₂₄H₂₈Cl₂N₄O [M+H]⁺ 459, found 459.

Step 3:4,6-dichloro-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine(3.44 g, 7.49 mmol), 5-chloropyridine-3-boronic acid (1.32 g, 08.39mmol), cesium carbonate (12.2 g, 37.4 mmol), and1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride (1.1 g,1.49 mmol) were combined in a vial that had been oven-dried and flushedwith nitrogen. Dioxane (75 mL) was added, and the vial was sealed andheated to 90° C. for 4 hours. The reaction mixture was cooled to roomtemperature, filtered over celite, and the filtrate was concentratedunder reduced pressure. The residue was purified by silica gelchromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford6-chloro-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine.MS ESI calc'd. for C₂₉H₃₁Cl₂N₅O [M+H]⁺ 536, found 536.

Step 4: In an oven-dried, nitrogen cooled flask were combinedpalladium(II) acetate (70 mg, 0.312 mmol) and(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (195 mg, 0.313mmol). N,N-dimethylacetamide (18.7 mL) was added, and the mixture wasdegassed for three minutes with nitrogen (sparge). Sulfuric acid (0.017mL) was added, and the mixture was degassed for three minutes withnitrogen (sparge). The flask was sealed and heated to 80° C. for 30minutes. The mixture was cooled to room temperature and added to aseparate nitrogen purged flask containing6-chloro-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine(1.68 g, 3.14 mmol), zinc cyanide (0.184 g, 1.57 mmol), and zinc (21 mg,0.32 mmol). The flask was purged with nitrogen for five minutes andsealed and heated to 100° C. for 3.5 hours. The reaction mixture wascooled to room temperature, filtered, diluted with ethyl acetate, andwashed with water and brine. The organic layer was dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel chromatography (0-100% ethyl acetate/hexanes,linear gradient) to afford4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ESI calc'd. for C₃₀H₃₁ClN₆O [M+H]⁺ 527, found 527.

Step 5: Hydroxylamine hydrochloride (5.4 mg, 0.08 mmol), sodiumbicarbonate (9.9 mg, 0.12 mmol), and water (0.12 mL) were combined in avial and stirred for 15 minutes. This solution was added to a vialcontaining4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(20.6 mg, 0.04 mmol) dissolved in ethanol (0.3 mL). The mixture wassealed and heated at 100° C. for 1 hour. The reaction was cooled to roomtemperature, quenched with water, and extracted with ethyl acetate (2×).The combined organic layers were dried over sodium sulfate, filtered,and concentrated to afford4-(5-chloropyridin-3-yl)-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide.MS ESI calc'd. for C₃₀H₃₄ClN₇O₂ [M+H]⁺ 560, found 560.

Step 6: To a solution of4-(5-chloropyridin-3-yl)-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide(21 mg, 0.04 mmol) and 1,1′-carbonyldiimidazole (6.1 mg, 0.04 mmol)dissolved in acetonitrile (1 mL) was added1,8-diazabicyclo[5.4.0]undec-7-ene (0.022 mL, 0.15 mmol). The reactionmixture was stirred at room temperature for 1 hour. The reaction waswashed with water and extracted with dichloromethane. The organic layerwas dried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by mass triggered, reverse phase(C-18) preparative HPLC (acetonitrile:water: 0.1% v/v trifluoroaceticacid modifier) to afford3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(as a TFA salt). MS ESI calc'd. for C₃₁H₃₂ClN₇O₃ [M+H]⁺ 586, found 586.¹H NMR (500 MHz, DMSO-d₆) δ 12.85 (s, 1H), 8.88 (d, J=1.6, 1H), 8.79 (d,J=2.3, 1H), 8.41 (t, J=2.0, 1H), 7.92 (s, 1H), 7.44 (d, J=7.4, 2H), 7.27(t, J=7.5, 2H), 7.20 (t, J=7.2, 1H), 4.88-4.81 (m, 1H), 4.05-3.74 (m,5H), 3.65-3.52 (m, 3H), 1.42-1.30 (m, 2H), 1.11-0.99 (m, 1H), 0.87-0.77(m, 1H), 0.74-0.58 (m, 5H), 0.57-0.51 (m, 1H), 0.49-0.42 (m, 1H),0.41-0.26 (m, 2H).

Example 2.2

5-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,3,4-oxadiazol-2(3H)-one

Step 1: Hydrochloric acid (3.0 M in methanol, 102 mL, 307 mmol) wasadded to4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(4.04 g, 7.67 mmol), and the mixture was stirred at 75° C. for 3.5hours. The reaction was cooled to room temperature, diluted withdichloromethane, and washed with saturated aqueous sodium bicarbonateand brine. The organic layer was dried over sodium sulfate, filtered,and concentrated under reduced pressure to afford methyl4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carboxylate.MS ESI calc'd. for C₃₁H₃₄ClN₅O₃ [M+H]⁺ 560, found 560.

Step 2: Hydrazine (9.2 mL, 293 mmol) was added to methyl4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carboxylate(4.11 g, 7.33 mmol) dissolved in methanol (36.6 mL), and the solutionwas stirred at room temperature for 30 minutes. The mixture was dilutedwith dichloromethane and washed with water and brine. The organic layerwas dried over sodium sulfate, filtered, and concentrated under reducedpressure to afford4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carbohydrazide.MS ESI calc'd. for C₃₀H₃₄ClN₇O₂ [M+H]⁺ 560, found 560.

Step 3: To a solution of4-[5-chloropyridin-3-yl)-3-(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl-3H-imidazo[4,5-c]pyridine-6-carbohydrazide(4.5 g, 8.03 mmol) and 1,1′-carbonyldiimidazole (1.43 g, 8.84 mmol)dissolved in acetonitrile (53.6 mL) was added1,8-diazabicyclo[5.4.0]undec-7-ene (4.8 mL, 32.1 mmol). The reactionmixture was stirred at room temperature for 1 hour. The reaction waswashed with water and extracted with dichloromethane. The organic layerwas dried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by silica gel chromatography (0-10%methanol/dichloromethane, and then 0-100% ethyl acetate/hexanes, lineargradient) to afford5-{4-[5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl-3H-imidazo[4,5-c]pyridin-6-yl}-1,3,4-oxadiazol-2(3H)-one.MS ESI calc'd. for C₃₁H₃₂ClN₇O₃ [M+H]⁺ 586, found 586. ¹H NMR (500 MHz,DMSO-d₆) δ 12.62 (s, 1H), 8.79 (d, J=8.3, 2H), 8.27 (s, 1H), 7.87 (s,1H), 7.42 (t, J=10.0, 2H), 7.25 (t, J=7.2, 2H), 7.22-7.17 (m, 1H), 4.76(s, 1H), 4.05-3.81 (m, 4H), 3.80-3.69 (m, 1H), 3.67-3.47 (m, 2H), 3.27(s, 1H), 1.37 (t, J=13.0, 2H), 1.03 (broad, 1H), 0.83 (broad, 1H), 0.68(d, J=6.2, 4H), 0.64-0.52 (m, 2H), 0.51-0.27 (m, 3H).

The following compounds in Table 2 (other than Example 2.1 and 2.2) wereprepared using procedures which were analogous to those described abovein Example 2.1 and Example 2.2

TABLE 2 FRET IC₅₀ Salt [M + H]⁺ [M + H]⁺ Ex. (nM) Structure ChemicalName Form Calc'd Obsv'd 2.1 <1

3-{4-(5- chloropyridin-3-yl)- 3-[(trans-4- methylcyclohexyl)methyl]-2-[(3R)-3- phenylmorpholin- 4-yl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 586 586 2.2  1

5-{4-(5- chloropyridin-3-yl)- 3-[(trans-4- methylcyclohexyl)methyl-2-[(3R)-3- phenylmorpholin- 4-yl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,3,4-oxadiazol- 2(3H)-one TFA 586 586 2.3  3

3-{3-[(trans-4- methylcyclohexyl) methyl]-4-(3- methylphenyl)-2-[(3R)-3- phenylmorpholin- 4-yl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one TFA 565 565 2.4  3

3-{4-(3- chlorophenyl)-3- [(trans-4- methylcyclohexyl)methyl]-2-[(3R)-3- phenylmorpholin- 4-yl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 585 585 2.5  9

5-{4-(3- chlorophenyl)-3- [(trans-4- methylcyclohexyl)methyl]-2-[(3R)-3- phenylmorpholin- 4-yl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,3,4-oxadiazol- 2(3H)-one TFA 585 585

Preparative Example 3.12-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile

Step 1:4,6-dichloro-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine(6.8 g, 22.8 mmol), 5-chloropyridine-3-boronic acid (3.95 g, 25.1 mmol),cesium carbonate (22.3 g, 68.4 mmol), and1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride (1.67 g,2.28 mmol) were combined in a vial that had been oven-dried and flushedwith nitrogen. Dioxane (73 mL) and water (18 mL) were added, and thevial was sealed and heated to 90° C. for 3 hours. The reaction mixturewas cooled to room temperature, diluted with ethyl acetate, and washedwith water. The organic layer was washed with brine, dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel chromatography (0-100% ethyl acetate/hexanes,linear gradient) to afford6-chloro-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine.MS ESI calc'd. for C₁₉H₂₀Cl₂N₄[M+H]⁺ 375, found 375.

Step 2: In an oven-dried, nitrogen cooled flask were placedpalladium(II) acetate (438 mg, 1.95 mmol) and(R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (1.22 g, 1.95 mmol).N,N-dimethylacetamide (98 mL) was added, and the flask was degassed forthree minutes with nitrogen (sparge). Sulfuric acid (0.104 mL, 1.95mmol) was added, and the flask was degassed for three minutes withnitrogen (sparge). The flask was sealed and heated to 80° C. for 30minutes. The mixture was cooled to room temperature and added to aseparate nitrogen purged flask containing6-chloro-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine(7.33 g, 19.5 mmol), zinc cyanide (1.15 g, 9.77 mmol), and zinc (128 mg,1.95 mmol). The flask was purged with nitrogen for five minutes, thensealed and heated to 100° C. for 3.5 hours. The reaction mixture wascooled to room temperature, filtered, diluted with ethyl acetate, andwashed with water and brine. The organic layer was dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel chromatography (0-100% ethyl acetate/hexanes,linear gradient) to afford4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ESI calc'd. for C₂₀H₂₀ClN₅ [M+H]⁺ 366, found 366.

Step 3: N-bromosuccinimide (5.84 g, 32.8 mmol) was added to a roomtemperature solution of4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(4 g, 10.9 mmol) stirring in degassed chloroform (54.7 mL). The reactionwas heated to reflux for 1 hour. The mixture was cooled to roomtemperature, diluted with dichloromethane, and washed with saturatedaqueous sodium thiosulfate (2×) and brine. The organic layer was driedover sodium sulfate, filtered, and concentrated under reduced pressure.The residue was purified by silica gel chromatography (0-100% ethylacetate/hexanes, linear gradient) to afford2-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ESI calc'd. for C₂₀H₁₉BrClN₅ [M+H]⁺ 444, found 444. ¹H NMR (500 MHz,DMSO-d₆) δ 8.87 (s, 1H), 8.84 (s, 1H), 8.57 (s, 1H), 8.40 (s, 1H), 3.86(d, J=6.1, 2H), 1.44 (d, J 12.1, 2H), 1.15-1.05 (broad, 1H), 1.00-0.85(broad, 1H), 0.85-0.73 (m, 4H), 0.72 (d, J=6.1, 3H), 0.56-0.43 (m 2H).

Alternatively, Step 3 could be performed as follows:

4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(1 g, 2.73 mmol) was dissolved in THF (10 mL). Disodium hydrogenphosphate (1.16 g, 8.20 mmol) was added and the reaction was warmed to35° C. with stirring. 1,3-dibromo-5,5-dimethylhydantoin (0.938 g, 3.28mmol) was added in 1 portion and the reaction was continued withstirring at 35° C. After 1 hour, the reaction was diluted with EtOAc(100 mL) and washed with aqueous NaHSO₃ and brine. The organic layer wasdried over Na₂SO₄, filtered, and concentrated. Purification of theresidue on a silica gel column with 0 to 75% EtOAc/hexanes provided2-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.

Preparative Example 3.2 benzyl(4aR,8aR)-octahydro-6H-pyrido[3,4-b][1,4]oxazine-6-carboxylate

Step 1: To N-Boc-4-hydroxypiperidine (2200 g, 10.95 mol) in anhydrousDCM (8 L) was added triethylamine (2284 mL, 16.42 mol) in one portion at0° C., then MsCl (1316 g, 11.49 mol) was added drop wise into themixture at 0° C. The mixture was stirred at room temperature for 2 h.Water (2 L) was added to the mixture and the organic phase wasseparated, and then the organic phase was washed with 1 M hydrochloridesolution (4 L), saturated NaHCO₃ solution (4 L), brine (1 L), and driedover anhydrous Na₂SO₄. The organic layer was concentrated to affordtert-butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate, which wasused for the next step without further purification.

Step 2: A solution of tert-butyl4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (312 g, 1.12 mol) andDBU (400 g, 2.24 mol) in THF (4.5 L) was heated to reflux overnight. Themixture was poured into ice-water (2 L) and then extracted with EtOAc (2L). The combined organic phase was washed with 1 M HCl solution (4L×2),aq. NaHCO₃ (4 L), and dried over anhydrous sodium sulfate. The residuewas concentrated to afford tert-butyl3,6-dihydropyridine-1(2H)-carboxylate, which was used in the next stepwithout further purification.

Step 3: To a solution of tert-butyl3,6-dihydropyridine-1(2H)-carboxylate (617 g, 3.37 mol) in anhydrous DCM(10 L) was added m-CPBA (989 g, 5.73 mol) in portions at 0° C. Themixture was stirred at room temperature for 1 hour. Saturated Na₂S₂O₃ (1L) was added and the organic layer was separated. The organic layer waswashed with 5% aqueous K₂CO₃ (5 L×2), brine (4 L), dried over sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by column chromatography (petroleum ether:ethylacetate=100:1-20:1) to obtain pure tert-butyl7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate.

Step 4: To a solution of tert-butyl7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (500 g, 2.5 mol) in H₂O(5 L) was added BnNH₂ (294 g, 2.75 mol) at room temperature. The mixturewas heated to reflux overnight. The mixture was extracted with DCM (1L), dried over sodium sulfate, and concentrated under reduced pressureto give tert-butyl-4-(benzylamino)-3-hydroxypiperidine-1-carboxylate andtert-butyl-3-(benzylamino)-4-hydroxypiperidine-1-carboxylate, which wereused in the next step without further purification.

Step 5: To a solution oftert-butyl-4-(benzylamino)-3-hydroxypiperidine-1-carboxylate andtert-butyl-3-(benzylamino)-4-hydroxypiperidine-1-carboxylate (153 g,0.42 mol, crude) and triethylamine (126 g, 1.25 mol) in DCM (800 mL) wasadded drop wise chloroacetyl chloride (33 g, 0.45 mol) at roomtemperature. The mixture was stirred at room temperature overnight. Themixture was quenched with water (300 mL) at 0° C., and extracted withDCM (500 mL×3). The organic layer was washed with brine (1 L), driedover sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography to afford tert-butyl4-[benzyl(chloroacetyl)amino]-3-hydroxypiperidine-1-carboxylate as amixture of trans diastereomers which was used directly in the next step.

Step 6: To a solution of trans-tert-butyl4-[benzyl(chloroacetyl)amino]-3-hydroxypiperidine-1-carboxylate (144 g,376 mmol) in CH₃CN (2 L) was added NaI (56.4 g, 376 mmol) in oneportion. The mixture was stirred at reflux for 1 h and thenconcentrated. The residue was dissolved in DCM (1 L) and filtered. Thefiltrate was concentrated under reduced pressure to affordtrans-tert-butyl4-[benzyl(iodoacetyl)amino]-3-hydroxypiperidine-1-carboxylate, which wasused directly in the next step without further purification.

Step 7: To a solution of trans-tert-butyl4-[benzyl(iodoacetyl)amino]-3-hydroxypiperidine-1-carboxylate (172 g,363 mmol) in THF (1500 mL) was added t-BuOK (48.72 g, 435 mmol) inportions at 0° C. The mixture was stirred at room temperature for 2 h.The mixture was poured into ice-water (400 mL) and extracted with EtOAc(200 mL×2). The organic layer was washed with brine (200 mL), dried oversodium sulfate, and concentrated under reduced pressure to givetert-butyl1-benzyl-2-oxooctahydro-6H-pyrido[3,4-b][1,4]oxazine-6-carboxylate as amixture of trans diastereomers, which was used in the next step withoutfurther purification.

Step 8: To a solution of trans-tert-butyl1-benzyl-2-oxooctahydro-6H-pyrido[3,4-b][1,4]oxazine-6-carboxylate (126g, 346 mmol) in anhydrous THF (2 L) was added borane methylsulfidecomplex (109 mL, 1.038 mol) drop wise at 0° C. The mixture was stirredat room temperature overnight. Methanol (300 mL) was added to themixture at room temperature and heated to reflux for 1 h. The mixturewas washed with saturated NaHCO₃ and brine, dried over sodium sulfate,and concentrated under reduced pressure. The residue was purified bysilica gel chromatography to afford tert-butyl1-benzyloctahydro-6H-pyrido[3,4-b][1,4]oxazine-6-carboxylate as amixture of trans diastereomers.

Step 9: To a mixture of trans-tert-butyl1-benzyloctahydro-6H-pyrido[3,4-b][1,4]oxazine-6-carboxylate (82 g, 246mmol) in EtOAc (500 mL) at 0° C. was added HCl in EtOAc (1500 mL, 4 M)dropwise. The reaction was stirred at room temperature for 2 hours. Themixture was concentrated to afford1-benzyloctahydro-1H-pyrido[3,4-b][1,4]oxazine as a mixture of transdiastereomers.

Step 10: To a solution oftrans-1-benzyloctahydro-1H-pyrido[3,4-b][1,4]oxazine (79 g, 0.34 mol)and TEA (72.1 g, 0.714 mol) in DCM (10 was added TFAA (78.5 g, 0.37 mol)dropwise at 0° C. The mixture was stirred at room temperature overnighttill the reaction was complete. The mixture was poured into water andextracted with DCM (500 mL×3). The combined organic layers were driedover sodium sulfate and concentrated to afford1-(1-benzyloctahydro-6H-pyrido[3,4-b][1,4]oxazin-6-yl)-2,2,2-trifluoroethanoneas a mixture of trans diastereomers, which was used in next step withoutfurther purification.

Step 11: A mixture oftrans-1-(1-benzyloctahydro-6H-pyrido[3,4-b][1,4]oxazin-6-yl)-2,2,2-trifluoroethanone(51.6 g, 0.15 mol), Pd/C (20 g) and (Boc)₂O (38.4 g, 0.176 mol) in MeOH(100 mL) was stirred at room temperature under H₂ (20 psi) for 6 h. Themixture was filtered, and the filtrate was concentrated under reducedpressure to give tert-butyl6-(trifluoroacetyl)octahydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylateas a mixture of trans diastereomers.

Step 12: To a solution of trans-tert-butyl6-(trifluoroacetyl)octahydro-1H-pyrido[3,4-[1,4]oxazine-1-carboxylate(70 g, 0.20 mol) in MeOH (160 mL) and water (600 mL) was added K₂CO₃(34.2 g, 0.24 mol) in one portion at room temperature. The mixture wasstirred for 2 h at room temperature, and then extracted with DCM (200mL×5). The combined organic layers were concentrated to give tert-butyloctahydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate as a mixture oftrans diastereomers. SFC purification afforded the pure S,S diastereomertert-butyl(4aS,8aS)-octahydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate (peak1)¹H NMR: (CDCl₃) δ 3.88-3.80 (m, 2H), 3.77-3.67 (m, 1H), 3.35-3.34 (m,2H), 3.29-3.27 (m, 2H), 3.10-3.11 (d, 1H), 2.54-2.42 (m, 3H), 1.76 (s,1H), 1.70-1.60 (m, 1H), 1.45 (s, 9H) LCMS (M+H)=243 and R,R diastereomertert-butyl(4aR,8aR)-octahydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate (peak2)¹H NMR: (CDCl₃) δ 3.89-3.80 (m, 2H), 3.77-3.67 (m, 1H), 3.35-3.34 (m,2H), 3.29-3.27 (m, 2H), 3.10-3.11 (d, 1H), 2.54-2.42 (m, 3H), 1.76 (s,1H), 1.70-1.60 (m, 1H), 1.44 (s, 9H) LCMS (M+H)=243.

Step 13: To tert-butyl(4aR,8aR)-octahydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate (250 mg,1.03 mmol) dissolved in DCM (2 mL) was added benzyl chloroformate (0.21mL, 1.44 mmol). Triethylamine (0.4 mL, 2.89 mmol) was added slowly andstirred for 3 hours at room temperature. The reaction was quenched withsaturated aqueous sodium bicarbonate. The aqueous layer was extractedwith DCM, and the combined organic layers were dried over sodiumsulfate, filtered, and concentrated to afford (4aR,8aR)-6-benzyl1-tert-butylhexahydro-1H-pyrido[3,4-b][1,4]oxazine-1,6(7H)-dicarboxylate. ¹H NMR(500 MHz, CDCl₃) δ 7.40-7.30 (m, 5H), 5.12 (s, 2H), 4.40-4.15 (m, 1H),3.93-3.87 (m, 1H), 3.86-3.79 (m, 1H), 3.77-3.71 (m, 1H), 3.42-3.29 (m,2H), 3.19-3.13 (m, 1H), 2.81-2.48 (m, 2H), 1.76-1.66 (m, 1H), 1.58 (s,2H), 1.45 (s, 9H).

Step 14: To (4aR,8aR)-6-benzyl 1-tert-butylhexahydro-1H-pyrido[3,4-b][1,4]oxazine-1,6(7H)-dicarboxylate (388 mg,1.03 mmol) dissolved in DCM (2.8 mL) was added TFA (0.57 mL). Thereaction was stirred at room temperature for 16 hours. The mixture wasconcentrated to afford benzyl(4aR,8aR)-octahydro-6H-pyrido[3,4-b][1,4]oxazine-6-carboxylate as a TFAsalt. MS ESI calc'd. for C₁₅H₂₀N₂O₃ [M+H]⁺ 277, found 277.

Preparative Example 3.3 7-azabicyclo[2.2.1]heptan-2-ol

Step 1: Into a 20-L 3-necked round-bottom flask were placed 1H-pyrrole(670.9 g, 10.00 mol, 1.00 equiv), CH₂Cl₂ (6000 ml), DMAP (61.09 g,500.04 mmol, 0.05 equiv) and Et₃N (1011.9 g, 10.00 mol, 1.00 equiv).Added a solution of (Boc)₂O (2400 g, 11.00 mol, 1.10 equiv) in CH₂Cl₂(2500 mL) dropwise with stirring at room temperature over 30 min. Theresulting solution was stirred for 5 hr at room temperature, then washedwith 2×500 mL of HCl (3%) and 2×500 mL of H₂O. The organic layer wasdried over anhydrous sodium sulfate and concentrated under vacuum. Thecrude product was purified by distillation under reduced pressure (20 mmHg), and a fraction was collected at 50° C. This resulted in tert-butyl1H-pyrrole-1-carboxylate as a yellow liquid.

Step 2: Into a 2000-mL 3-necked round-bottom flask was placed methyl3-bromopropiolate (120 g, 736.33 mmol, 1.00 equiv) and tert-butyl1H-pyrrole-1-carboxylate (615.61 g, 3.68 mol, 5.00 equiv). The resultingsolution was stirred for 30 hr at 95° C. in an oil bath. The reactionmixture was cooled and distilled under reduced pressure (20 mm Hg). Thefraction collected at 55° C. was purified by silica gel chromatography(ethyl acetate/petroleum ether, 1:20) to afford 7-tert-butyl 2-methyl3-bromo-7-azabicyclo[2.2.1]hepta-2,5-diene-2,7-dicarboxylate as a yellowliquid.

Step 3: Into a 2000-mL 3-necked round-bottom flask purged and maintainedwith an inert atmosphere of nitrogen was placed 7-tert-butyl 2-methyl3-bromo-7-azabicyclo[2.2.1]hepta-2,5-diene-2,7-dicarboxylate (70 g,212.01 mmol, 1.00 equiv), acetonitrile (700 mL) and triethylamine(107.26 g, 1.06 mol, 5.00 equiv). Diethylamine (17.06 g, 233.25 mmol,1.10 equiv) was added dropwise with stirring at room temperature over 60min, followed by addition of HCl (700 mL) dropwise with stirring at roomtemperature over 30 min. The resulting solution was stirred for 4 hr atroom temperature, then quenched by the addition of 700 mL of water. Theresulting solution was extracted with 3×700 mL of dichloromethane. Theorganic layers were combined, dried, and concentrated under vacuum toafford 7-tert-butyl 2-methyl3-oxo-7-azabicyclo[2.2.1]hept-5-ene-2,7-dicarboxylate.

Step 4: A mixture of 7-tert-butyl 2-methyl3-oxo-7-azabicyclo[2.2.1]hept-5-ene-2,7-dicarboxylate (50 g, 187.07mmol, 1.00 equiv), MeOH (500 mL), and Pd/C (5 g, 10%) was stirredovernight at room temperature under a hydrogen atmosphere. The reactionwas filtered, and the filtrate was concentrated under vacuum to afford7-tert-butyl 2-methyl3-oxo-7-azabicyclo[2.2.1]heptane-2,7-dicarboxylate.

Step 5: Into a 2000-mL 3-necked round-bottom flask purged and maintainedwith an inert atmosphere of nitrogen was placed 7-tert-butyl 2-methyl3-oxo-7-azabicyclo[2.2.1]heptane-2,7-dicarboxylate (121.82 g, 452.37mmol, 1.00 equiv) and HCl (1200 mL, 10%). The resulting solution wasstirred for 3 hr at 105° C. in an oil bath, then cooled and concentratedunder vacuum to afford 7-aza-bicyclo[2.2.1] heptan-2-one.

Step 6: Into a 2000-mL 3-necked round-bottom flask purged and maintainedwith an inert atmosphere of nitrogen was placed 7-aza-bicyclo[2.2.1]heptan-2-one (39.72 g, 357.39 mmol, 1.00 equiv), DCM (400 mL),triethylamine (146.47 g, 1.45 mol, 4.05 equiv), and (Boc)₂O (156.01 g,714.82 mmol, 2.00 equiv). The resulting solution was stirred for 2 h atroom temperature. The resulting mixture was washed with 1×400 mL ofNa₂CO₃ solution and 1×400 mL of H₂O. The organic layer was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waspurified by silica gel chromatograpy (ethyl acetate/petroleum ether,10:1) to afford tert-butyl2-oxo-7-azabicyclo[2.2.1]heptane-7-carboxylate.

Step 7: To a solution of tert-butyl2-oxo-7-azabicyclo[2.2.1]heptane-7-carboxylate (500 mg, 2.37 mmol) inmethanol (4.7 mL) at 0° C. was added sodium borohydride (134 mg, 3.55mmol). The reaction mixture was stirred at 0° C. for 1 hour and thenstirred for 16 hours at room temperature. The mixture was quenched withsaturated aqueous ammonium chloride and concentrated. The resultingresidue was extracted with DCM (3×) and the combined extracts were driedover sodium sulfate, filtered, and concentrated to afford tert-butyl2-hydroxy-7-azabicyclo[2.2.1]heptane-7-carboxylate. ¹H NMR (500 MHz,CDCl₃) δ 4.35 (broad, 1H), 4.13 (s, 2H), 2.28-2.19 (m, 1H), 2.18-2.12(m, 1H), 1.83-1.75 (m, 1H), 1.71-1.68 (m, 1H), 1.66-1.56 (m, 1H),1.56-1.48 (m, 1H), 1.44 (s, 9H), 1.05 (dd, J=3.4, 12.7, 1H).

Step 8: To tert-butyl 2-hydroxy-7-azabicyclo[2.2.1]heptane-7-carboxylate(505 mg, 2.37 mmol) dissolved in DCM (5.9 mL) was added TFA (1.9 mL).The reaction was stirred for 16 hours at room temperature. The mixturewas concentrated to give 7-azabicyclo[2.2.1]heptan-2-ol.

Preparative Example 3.4 (3R,5S)-5-(propan-2-yl)pyrrolidin-3-ol

Step 1: Thionyl chloride (270 mL) was added dropwise to methanol (1500mL) over 1 hour, followed by the addition of (4R)-4-hydroxy-L-proline(150 g). The mixture was stirred at reflux for 36 hours, and thenconcentrated under reduced pressure. Methanol (1500 mL) was added,followed by a slow addition of triethylamine (310 mL). The mixture wascooled to 0° C., filtered, and the filtrate was concentrated to affordmethyl (4R)-4-hydroxy-L-prolinate. The residue was used directly withoutfurther purification.

Step 2: To a solution of methyl (4R)-4-hydroxy-L-prolinate (120 g) intetrahydrofuran (500 mL) at 0° C. was added triethylamine (180 mL)dropwise. The solution was stirred at 0° C. for 15 minutes, thendi-tert-butyl dicarbonate (130 g) dissolved in tetrahydrofuran (100 mL)was added at 0° C. over 1 hour. The mixture was stirred at 0° C. for 1hour. Upon completion the mixture was filtered. The filtrate wasconcentrated, dissolved in ethyl acetate, and washed with water. Theaqueous layer was extracted with ethyl acetate (2×), and the combinedorganic layers were washed with brine, dried over sodium sulfate,filtered, and concentrated to give 1-tert-butyl 2-methyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate. The residue was useddirectly without further purification.

Step 3: To a solution of 1-tert-butyl 2-methyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (970 g) inN,N-dimethylformamide (1000 mL) was added imidazole (591 g) at 0° C.Upon dissolution of the imidazole, tert-butyldimethylsilyl chloride (652g) was added at 0° C. The reaction was stirred for 16 hours at roomtemperature, cooled to 0° C., and quenched with water (2.25 L). Themixture was extracted with ethyl acetate (4×), and the combined organiclayer was washed with brine (3×), dried over magnesium sulfate,filtered, and concentrated to give 1-tert-butyl 2-methyl(2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}pyrrolidine-1,2-dicarboxylate.The residue was used directly without further purification.

Step 4: To magnesium (76 g) in a three-neck flask was added ether tocover the solid. Iodomethane (200 mL) was added dropwise to maintainreflux of the ether, and the mixture was stirred at 30° C. for 1 hour. Asolution of 1-tert-butyl 2-methyl(2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}pyrrolidine-1,2-dicarboxylate(280 g) in ether (200 mL) was added dropwise over 3 hours at 0° C. Themixture was stirred at room temperature for 1 hour, and then it waspoured into a solution of saturated aqueous ammonium chloride slowly.The organic layer was separated and the aqueous layer was extracted withethyl acetate (2×). The combined organic layer was washed with brine,dried over sodium sulfate, filtered, and concentrated to give tert-butyl(2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(2-hydroxypropan-2-yl)pyrrolidine-1-carboxylate.The residue was used directly without further purification.

Step 5: To a solution of tert-butyl(2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(2-hydroxypropan-2-yl)pyrrolidine-1-carboxylate(98 g) dissolved in toluene (900 mL) at −78° C. was added triethylamine(310 mL). The mixture was stirred at −78° C. for 10 minutes, and thenthionyl chloride (60 mL) in toluene (100 mL) was added dropwise over 1.5hours. The mixture was stirred at −78° C. for 2 hours and then quenchedwith saturated ammonium chloride. The aqueous layer was extracted withethyl acetate, and the organic layer was washed with saturated aqueoussodium bicarbonate and brine. The organic layer was dried over sodiumsulfate, filtered, and concentrated to give tert-butyl(2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(prop-1-en-2-yl)pyrrolidine-1-carboxylate.The residue was used directly without further purification.

Step 6: To a solution of tert-butyl(2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(prop-1-en-2-yl)pyrrolidine-1-carboxylate(90 g) dissolved in methanol (250 mL) was added Raney Nickel (24 g). Thereaction mixture was stirred under hydrogen (40 atm) at 60° C. for 3hours. The mixture was filtered and concentrated under reduced pressure.The residue was dissolved in ethyl acetate, washed with brine (2×50 mL),dried over magnesium sulfate, filtered and concentrated to givetert-butyl

(2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(propan-2-yl)pyrrolidine-1-carboxylate.The residue was used directly without further purification.

Step 7: To a solution of tert-butyl(2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(propan-2-yl)pyrrolidine-1-carboxylate(50 g) dissolved in tetrahydrofuran was added tetra-N-butylammoniumfluoride (95 g) dissolved in tetrahydrofuran (250 mL) at 0° C. Themixture was stirred for 16 h at room temperature and then quenched withwater (100 mL). The solution was washed with hydrochloric acid (6 N),extracted with ethyl acetate (3×100 mL), dried over magnesium sulfate,filtered, and concentrated. The residue was purified by silica gelchromatography (2/1 petroleum ether/ethyl acetate) to afford tert-butyl(2S,4R)-4-hydroxy-2-(propan-2-yl)pyrrolidine-1-carboxylate.

Step 8: To a solution of tert-butyl(2S,4R)-4-hydroxy-2-(propan-2-yl)pyrrolidine-1-carboxylate (500 mg,2.180 mmol) dissolved in dichloromethane (5.4 mL) was addedtrifluoroacetic acid (1.8 mL). The reaction was stirred for 16 hours atroom temperature. The mixture was concentrated to afford(3R,5S)-5-(propan-2-yl)pyrrolidin-3-ol as a TFA salt. ¹H NMR (500 MHz,CDCl₃) δ 3.91-3.62 (m, 1H), 3.60-3.36 (m, 2H), 2.47-2.10 (m, 2H),2.05-1.79 (m, 2H), 1.07 (d, J=6.6, 3H), 1.01 (d, J=6.7, 3H).

Preparative Example 3.5 (5S)-3-methyl-5-(propan-2-yl)pyrrolidin-3-ol

Step 1: Oxalyl chloride (16 mL) dissolved in DCM (200 mL) was placed ina three-neck flask equipped with a stirrer and two addition funnels. Onefunnel contained DMSO (23 mL) in DCM (100 mL) and the other tert-butyl(2S,4R)-4-hydroxy-2-(propan-2-yl)pyrrolidine-1-carboxylate (37 g) in DCM(100 mL). The contents of the flask were cooled to −78° C., and the DMSOsolution was added dropwise. After 15 minutes, tert-butyl(2S,4R)-4-hydroxy-2-(propan-2-yl)pyrrolidine-1-carboxylate was added.The reaction mixture was stirred for 30 minutes, and triethylamine (110mL) was added. The cooling bath was removed, and water (100 mL) wasadded at room temperature and stirred for 10 minutes. The organic layerwas separated, and the aqueous layer was extracted with DCM (3×100 mL).The combined organic layers were washed with brine (3×50 mL), dried overmagnesium sulfate, filtered, and concentrated. The material was purifiedby silica gel chromatography (petroleum ether/ethyl acetate, 15/1) toafford tert-butyl (2S)-4-oxo-2-(propan-2-yl)pyrrolidine-1-carboxylate.

Step 2: To a solution of tert-butyl(2S)-4-oxo-2-(propan-2-yl)pyrrolidine-1-carboxylate (500 mg, 2.2 mmol)in THF (10 mL) at −78° C. was added methylmagnesium bromide (1.65 mL,4.95 mmol) dropwise. The reaction was stirred at −78° C. for 2 hoursbefore warming to room temperature and stirring for an additional 2hours. The reaction was quenched by slowly adding saturated aqueousammonium chloride at 0° C. The mixture was acidified with HCl (1 N) andextracted with ethyl acetate (2×). The combined organic layers werewashed with brine, dried over sodium sulfate, filtered, andconcentrated. The residue was purified by silica gel chromatography(0-80% ethylacete/hexanes, linear gradient) to afford tert-butyl(2S)-4-hydroxy-4-methyl-2-(propan-2-yl)pyrrolidine-1-carboxylate.

Step 3: To tert-butyl(2S)-4-hydroxy-4-methyl-2-(propan-2-yl)pyrrolidine-1-carboxylate (532.2mg, 2.18 mmol) dissolved in DCM (5.5 mL) was added TFA (1.8 mL). Themixture was stirred for 16 hours. The mixture was concentrated to give(5S)-3-methyl-5-(propan-2-yl)pyrrolidin-3-ol as a TFA salt. ¹H NMR (500MHz, CDCl₃) δ 3.76 (s, 1H), 3.49-3.34 (m, 2H), 2.29-2.17 (m, 1H),2.06-1.95 (m, 2H), 1.51 (s, 3H), 1.07-0.97 (m, 7H).

Preparative Example 3.6 (3R,5S)-5-(hydroxymethyl)pyrrolidin-3-ol

Step 1: Into a 20000-mL 4-necked round-bottom flask, was placed asolution of methyl (2S,4R)-4-hydroxypyrrolidine-2-carboxylatehydrochloride (1000 g, 5.51 mol, 1.00 equiv) in dichloromethane (8000mL). This was followed by the addition of triethylamine (1680 g, 16.60mol, 3.00 equiv) dropwise with stirring at <20° C. The resultingsolution was stirred for 1 h at room temperature. To this was addeddi-tert-butyl dicarbonate (1446 g, 1.20 equiv) in several batches at 0°C. The resulting solution was stirred overnight at room temperature. Theresulting solution was washed with 3×5000 mL of water, 2×5000 mL ofhydrogen chloride (1 N), 2×5000 mL of sodium bicarbonate(aq) and 2×5000mL of brine. The mixture was dried over anhydrous sodium sulfate andconcentrated under vacuum. The crude product was purified byrecrystallization from petroleum ether (3000 mL). This resulted in1-tert-butyl 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate asa white solid.

Step 2: Into a 3000-mL 4-necked round-bottom flask, purged andmaintained with an inert atmosphere of nitrogen, was placed a solutionof LiBH₄ (16.2 g, 736.36 mmol, 1.50 equiv) in tetrahydrofuran (500 mL).This was followed by the addition of a solution of 1-tert-butyl 2-methyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (120 g, 489.25 mmol, 1.00equiv) in tetrahydrofuran (700 mL) dropwise with stirring at <5° C. Theresulting solution was stirred overnight at room temperature. Thereaction was then quenched by the addition of 2000 mL of water. Theresulting solution was extracted with 2×500 mL of ethyl acetate. Thecombined organic layers were washed with 2×500 mL of brine. The organiclayer was dried over anhydrous sodium sulfate and concentrated undervacuum. The crude product was purified by re-crystallization fromhexane. This resulted in tert-butyl(2S,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate as a whitesolid. ¹H NMR (300 MHz, DMSO-d₆) δ 4.84 (s, 1H), 4.64-4.66 (d, 1 H,J=5.7 Hz), 4.18-4.23 (m, 1H), 3.75 (s, 1H), 3.36-3.45 (m, 2H), 3.21-3.24(t, 2H, J=5.1 Hz), 1.87-2.02 (m, 2H), 1.39 (s, 9H).

Step 3: To tert-butyl(2S,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (498.5 mg,2.29 mmol) dissolved in DCM (6.8 mL) was added TFA (0.85 mL). Themixture was stirred for 16 hours. The mixture was concentrated to give(3R,5S)-5-(hydroxymethyl)pyrrolidin-3-ol as a TFA salt.

Preparative Example 3.7 4-methoxy-2-(1-methoxycyclopropyl)pyrrolidine

Step 1: To a mixture of 1-benzyl 2-methyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (500 mg, 1.79 mmol) inTHF (6 mL) was added methyl iodide (0.385 mL) followed by sodium hydride(95 mg, 3.94 mmol). The reaction was stirred for 1 hour, then quenchedwith ice and diluted with diethyl ether. The organic layer was washedwith water and brine, dried over sodium sulfate, filtered, andconcentrated under reduced pressure to afford 1-benzyl 2-methyl4-methoxypyrrolidine-1,2-dicarboxylate. MS ESI calc'd. for C₁₅H₁₉NO₅[M+H]⁺ 294, found 294.

Step 2: A 3M solution of ethylmagnesium bromide (1.43 mL, 4.30 mmol) wasadded over a period of 40-60 minutes under stirring to a roomtemperature solution of 1-benzyl 2-methyl4-methoxypyrrolidine-1,2-dicarboxylate (420 mg, 1.43 mmol) and titanium(IV) isopropoxide (0.086 mL, 0.286 mmol) in diethyl ether. The mixturewas stirred for 1 hour at room temperature. The reaction was cooled to0° C., treated with a few drops of saturated aqueous ammonium chloride,filtered through celite, and washed with diethyl ether. The organiclayer was dried over sodium sulfate, filtered, and concentrated underreduced pressure to afford benzyl241-hydroxycyclopropyl)-4-methoxypyrrolidine-1-carboxylate. MS ESIcalc'd. for C₁₆H₂₁Na₄ [M+H]⁺ 292, found 292.

Step 3: To a mixture of benzyl2-(1-hydroxycyclopropyl)-4-methoxypyrrolidine-1-carboxylate (312 mg,1.07 mmol) dissolved in THF (3.6 mL) at 0° C. was added methyl iodide(0.23 mL, 3.68 mmol) followed by sodium hydride (56.5 mg, 2.36 mmol).The mixture was stirred for 2 hours at room temperature. The reactionwas quenched with ice, and diluted with diethyl ether. The organic layerwas washed with water and brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (0-20% methanol/dichloromethane, linear gradient) toafford benzyl4-methoxy-2-(1-methoxycyclopropyl)pyrrolidine-1-carboxylate. MS ESIcalc'd. for C₁₇H₂₃NO₄ [M+H]⁺ 306, found 306.

Step 4: To benzyl4-methoxy-2-(1-methoxycyclopropyl)pyrrolidine-1-carboxylate (141 mg,0.462 mmol) dissolved in ethyl acetate (3.1 mL) was added palladium oncarbon (49.1 mg, 0.05 mmol). Hydrogen gas was added via balloon and thereaction was stirred at room temperature for 3 hours. The mixture wasfiltered over celite and concentrated under reduced pressure to afford4-methoxy-2-(1-methoxycyclopropyl)pyrrolidine.

Preparative Example 3.8 decahydroquinolin-3-ol

3-Quinolinol (10 g) was dissolved in THF (180 ml) and hydrogenated overRaney —Ni (3.0 g) with an initial pressure of 110 kg/cm². The reactionwas heated to 150° C. during which time the pressure rose to 120 kg/cm²and these conditions were maintained for 24 hr. After cooling, thesolution was filtered through Celite, and the solvent was removed invacuo leaving 10 g of oil. After standing, the oil solidified. A smallamount of EtOAc was added, and the solid was removed by filtration andwashed with EtOAc to give decahydroquinolin-3-ol as a white solid.¹H-NMR (300 MHz, CDCl₃): δ1.07-1.33 (m, 5H), 1.57-2.05 (m, 7H),2.39-2.47 (t, 1H), 3.18-3.24 (m, 1H), 3.63-3.73 (m, 1H)

Preparative Example 3.9 2-(1-methoxyethyl)pyrrolidine

Step 1: To a mixture of tert-butyl2-(1-hydroxyethyl)pyrrolidine-1-carboxylate (750 mg, 3.48 mmol) in DMF(12 mL) at 0° C. was added methyl iodide (0.75 mL, 11.98 mmol) followedby sodium hydride (184 mg, 7.66 mmol). The mixture was stirred for 2hours at room temperature. The reaction was quenched with ice anddiluted with diethyl ether. The organic layer was washed with water andbrine, dried over sodium sulfate, and filtered and concentrated underreduced pressure to afford tert-butyl2-(1-methoxyethyl)pyrrolidine-1-carboxylate. ¹H NMR (500 MHz, CDCl₃) δ3.92-3.45 (m, 2H), 3.45-3.23 (m, 4H), 2.11-1.66 (m, 4H), 1.63 (s, 1H),1.46 (s, 9H), 1.04 (dd, J=6.3, 30.8, 3H).

Step 2: To tert-butyl 2-(1-methoxyethyl)pyrrolidine-1-carboxylate (827mg, 3.61 mmol) dissolved in DCM (15 mL) was added TFA (0.83 mL). Themixture was stirred for 16 hours. The reaction was concentrated, dilutedwith DCM, and washed with HCl (1 N). The combined organic layers weredried over sodium sulfate, filtered, and concentrated under reducedpressure to afford 2-(1-methoxyethyl)pyrrolidine.

Preparative Example 3.10 (2S,4R)-2-(fluoromethyl)-4-methoxypyrrolidine

Step 1: To a solution of benzyl(2S,4R)-2-(fluoromethyl)-4-hydroxypyrrolidine-1-carboxylate (500 mg,1.97 mmol) in THF (6.6 mL) at 0° C. was added methyl iodide (0.43 mL,3.44 mmol) followed by sodium hydride (104 mg, 4.34 mmol). The mixturewas stirred for 2 hours at room temperature. The reaction was quenchedwith ice, and diluted with diethyl ether. The organic layer was washedwith water and brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure to afford benzyl(2S,4R)-2-(fluoromethyl)-4-methoxypyrrolidine-1-carboxylate. MS ESIcalc'd. for C₁₄H₁₈FNO₃ [M+H]⁺ 268, found 268.

Step 2: To benzyl(2S,4R)-2-(fluoromethyl)-4-methoxypyrrolidine-1-carboxylate (529 mg,1.98 mmol) dissolved in ethyl acetate (12.9 mL) was added palladium oncarbon (211 mg, 0.2 mmol). Hydrogen gas was added via balloon, and thereaction was stirred at room temperature for 3 hours. The mixture wasfiltered over celite and concentrated under reduced pressure to afford(2S,4R)-2-(fluoromethyl)-4-methoxypyrrolidine. ¹H NMR (500 MHz, CDCl₃) δ4.44-4.19 (m, 2H), 3.29 (s, 3H), 3.09-2.93 (m, 2H), 2.02-1.92 (m, 1H),1.78 (s, 2H), 1.62-1.56 (m, 1H), 1.25 (s, 1H).

Preparative Example 3.11 (2R)-5-methoxy-2-methylpiperidine

Step 1: To a solution of 6-methylpyridin-3-ol (20.0 g, 0.183 mol) inMeOH (200 mL) were added concentrated HCl (15.43 mL, 0.1850 mol) andPtO₂ (2.40 g, 0.011 mol). The resulting mixture was heated to 70° C. at50 PSI overnight. The reaction was filtered to remove the PtO₂ andconcentrated to a solid to provide ±trans-6-methylpiperidin-3-olhydrochloride. The crude solid was taken on without furtherpurification.

Step 2: A mixture of ±trans-6-methylpiperidin-3-ol hydrochloride (14.0g, 0.092 mol) in CH₂Cl₂ (150 mL) was cooled to 0° C. Triethylamine (51.5mL, 0.369 mol) was added slowly. CbzCl (13.59 mL, 0.092 mol) was addeddropwise, keeping the temperature below 20° C. The reaction was allowedto warm overnight to room temperature. The reaction was quenched byaddition of water and diluted further with additional CH₂Cl₂. The layerswere separated and the organics were dried over MgSO₄ and concentrated.The crude material was purified by silica gel gradient chromatography(0-75% ethyl acetate in hexanes), providing ±Benzyltrans-5-hydroxy-2-methylpiperidine-1-carboxylate.

Step 3: To a solution of oxalyl chloride (13.17 mL, 0.150 mol) in CH₂Cl₂(250 mL) at −78° C. was added DMSO (14.23 mL, 0.201 mol) dropwise. Thereaction was aged for 20 min at −78° C., then ±Benzyltrans-5-hydroxy-2-methylpiperidine-1-carboxylate (25.0 g, 0.100 mol) wasadded dropwise over 10 min and aged for an additional 10 min beforetriethylamine (41.9 mL, 0.301 mol) was added dropwise over 5 min at −78°C. The reaction was warmed to room temperature, then quenched withaddition of half-saturated, aqueous NaHCO₃ and additional CH₂Cl₂. Thelayers were separated, and the organics were dried with MgSO₄ andconcentrated. The crude material was purified by silica gel gradientchromatography (0-50% ethyl acetate in hexanes), providing ±benzyl2-methyl-5-oxopiperidine-1-carboxylate.

Step 4: To a solution of THF (200 mL) and MeOH (11 mL) was added LiBH₄(2 M, 89 mL, 0.18 mol). Some gas evolution and a small exotherm wereobserved. The reaction was aged at room temperature for 30 min beforebeing cooled to −10° C.±benzyl 2-methyl-5-oxopiperidine-1-carboxylate(22.0 g, 0.089 mol) was then added dropwise, keeping the temperaturebelow −5° C. The reaction was then aged at −10° C. for 30 min. Thereaction was quenched by adding half-saturated, aqueous NaHCO₃, thenextracted with EtOAc. The layers were separated and the organics driedwith MgSO₄. The organics were concentrated to give crude±benzyl-5-hydroxy-2-methylpiperidine-1-carboxylate as a crude, colorlessoil.

Step 5: Chiral separation (SFC, IC 30×250 mm, 15% MeOH/CO₂, 70 ml/min,115 mg/ml in MeOH) of thecrude±benzyl-5-hydroxy-2-methylpiperidine-1-carboxylate provided benzyl(2R,5S)-5-hydroxy-2-methylpiperidine-1-carboxylate as enantiopurematerial.

Step 6: Benzyl (2R,5S)-5-hydroxy-2-methylpiperidine-1-carboxylate (6.8g, 27.3 mmol) was dissolved in DCM (100 mL) containing crushed molecularsieves. N-methylmorpholine N-oxide (4.15 g, 35.5 mmol) andtetrapropylammonium perruthenate (0.48 g, 1.36 mmol) were added, and thereaction was stirred at room temperature for 1.5 hours. The mixture wasfiltered through a celite pad and concentrated. The residue was purifiedby silica gel chromatography (0-30% ethyl acetate/hexanes, lineargradient) to afford benzyl (2R)-2-methyl-5-oxopiperidine-1-carboxylate.MS ESI calc'd. for C₄H₁₇NO₃ [M+H]⁺ 248, found 248.

Step 7: To a solution of benzyl(2R)-2-methyl-5-oxopiperidine-1-carboxylate (365 mg, 1.47 mmol) inmethanol (2.9 mL) at 0° C. was added sodium borohydride (84 mg, 2.21mmol). The reaction mixture was stirred at 0° C. for 1 hour and thenstirred for 16 hours at room temperature. The mixture was quenched withsaturated aqueous ammonium chloride and concentrated. The resultingresidue was extracted with DCM (3×) and the combined extracts were driedover sodium sulfate, filtered, and concentrated to afford benzyl(2R)-5-hydroxy-2-methylpiperidine-1-carboxylate. MS ESI calc'd. forC₁₄H₁₉NO₃ [M+H]⁺ 250, found 250.

Step 8: To a mixture of benzyl(2R)-5-hydroxy-2-methylpiperidine-1-carboxylate (368 mg, 1.47 mmol)dissolved in THF (4.9 mL) at 0° C. was added methyl iodide (0.32 mL,5.08 mmol) followed by sodium hydride (78 mg, 3.25 mmol). The mixturewas stirred for 2 hours at room temperature. The reaction was quenchedwith ice, and diluted with diethyl ether. The organic layer was washedwith water and brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure to afford benzyl(2R)-5-methoxy-2-methylpiperidine-1-carboxylate. MS ESI calc'd. forC₁₆H₂₁NO₃ [M+H]⁺ 264, found 264.

Step 9: To benzyl (2R)-5-methoxy-2-methylpiperidine-1-carboxylate (345mg, 1.31 mmol) dissolved in ethyl acetate (6.5 mL) was added palladiumon carbon (139 mg, 0.13 mmol). Hydrogen gas was added via balloon, andthe reaction was stirred at room temperature for 3 hours. The mixturewas filtered over celite and concentrated under reduced pressure toafford (2R)-5-methoxy-2-methylpiperidine. ¹H NMR (500 MHz, DMSO-d₆) δ3.33 (s, 3H), 3.23-3.13 (m, 2H), 2.66-2.59 (m, 1H), 2.03-1.97 (m, 1H),1.47-1.40 (m, 1H), 1.39-1.28 (m, 2H), 1.08-1.04 (m, 3H), 0.91-0.79 (m,2H).

Preparative Example 3.12trans-5,5-difluorooctahydrocyclopenta[b][1,4]oxazine hydrochloride

Step 1: To a stirred solution of cyclopent-2-enone (1.70 g, 20.7 mmol)in CH₂Cl₂ (20 mL), bromine (3.27 g, 20.7 mmol) in CH₂Cl₂ (10 mL) andEt₃N (3.29 g, 31.1 mmol) in CH₂Cl₂ (10 mL) were added at 0° C. under anitrogen atmosphere. The reaction mixture was gradually warmed to roomtemperature and stirred for 2 hours. The reaction mixture was filteredthrough celite, washing with CH₂Cl₂, and the filtrate was concentratedin vacuo. Purification of the residue on a silica gel column with 0 to20% EtOAc/Hexanes afforded 2-bromocyclopent-2-enone.

Step 2: To a stirred solution of 2-bromocyclopent-2-enone (1.00 g, 6.21mmol) in H₂O (25 mL), tetrabutylammonium bromide (400 mg, 1.24 mmol) andbenzyl amine (790 mg, 7.45 mmol) were added at room temperature. Thereaction mixture was stirred for 24 hours and then extracted with EtOAc(100 mL). The organic layer was separated, washed with brine, and driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. Purificationof the residue on a silica gel column with 0 to 30% EtOAc/Hexanesafforded 6-benzyl-6-azabicyclo[3.1.0]hexan-2-one. MS ESI calc'd. forC₁₂H₁₃NO [M+H]⁺ 188, found 188.

Step 3: 6-benzyl-6-azabicyclo[3.1.0]hexan-2-one (50 mg, 0.26 mmol) wasdissolved in toluene (1.0 mL) and DAST (215 mg, 1.33 mmol) was addeddropwise. The reaction was then heated at 60° C. for 5 hours, cooled to0° C. and quenched by adding saturated aqueous NaHCO₃ solution (2 mL).The layers were separated, and the aqueous layer was extracted usingEtOAc (10 mL). The combined organic layers were washed with brine, driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. Purificationof the residue on a silica gel column with 0 to 20% EtOAc/Hexanesafforded 6-benzyl-2,2-difluoro-6-azabicyclo[3.1.0]hexane. MS ESI calc'd.for C₁₂H₁₃F₂N [M+H]⁺ 210, found 210.

Step 4: To a stirred solution of6-benzyl-2,2-difluoro-6-azabicyclo[3.1.0]hexane (25 mg, 0.11 mmol) inCH₃CN (1 mL), acetic acid (1 mL) was added at room temperature. Thereaction mixture was heated to 80° C. for 16 h, cooled to roomtemperature and concentrated in vacuo. Purification of the residue on asilica gel column with 0 to 20% EtOAc/Hexanes affordedtrans-2-(benzylamino)-3,3-difluorocyclopentyl acetate. MS ESI calc'd.for C₁₄H₁₇F₂NO₂ [M+H]⁺ 270, found 270.

Step 5: To a stirred solution oftrans-2-(benzylamino)-3,3-difluorocyclopentyl acetate (100 mg, 0.37mmol) in CH₃OH (2 mL), K₂CO₃ (52 mg, 0.37 mmol) was added at roomtemperature. The reaction mixture was stirred at room temperature for 1hour and concentrated in vacuo. The residue was dissolved in CH₂Cl₂,washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to affordtrans-2-(benzylamino)-3,3-difluorocyclopentanol. MS ESI calc'd. forC₁₂H₁₅F₂NO [M+H]⁺ 228, found 228.

Step 6: Triethylamine (1.84 mL, 13.2 mmol) was added to a solution oftrans-2-(benzylamino)-3,3-difluorocyclopentanol (500 mg, 2.2 mmol) indichloromethane (20 mL) at −40° C., followed by the addition of2-chloroacetyl chloride (547 mg, 4.8 mmol) dropwise to the reaction. Thereacton mixture was stirred at −40° C. for 3 hours and then warmed to 0°C.; this temperature was maintained for 2 hours. The reaction mixturewas quenched with saturated aqueous NaHCO₃ solution. The layers wereseparated, and the aqueous layer was extracted with dichloromethane(3×20 mL). The combined organic layers were washed with brine, driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. Purificationof the residue on a silica gel column (0 to 30% EtOAc/hexanes) affordedtrans-2-(N-benzyl-2-chloroacetamido)-3,3-difluorocyclopentyl2-chloroacetate. MS ESI calc'd. for C₁₆H₁₇Cl₂F₂NO₃ [M+H]⁺ 380, found380.

Step 7: To a stirred solution oftrans-2-(N-benzyl-2-chloroacetamido)-3,3-difluorocyclopentyl2-chloroacetate (480 mg, 1.26 mmol) in CH₃OH (15 mL), K₂CO₃ (175 mg,1.26 mmol) was added at room temperature. The reaction mixture wasstirred at room temperature for 3 hours and then concentrated in vacuo.The residue was dissolved in CH₂Cl₂, washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to affordtrans-N-benzyl-2-chloro-N-(2,2-difluoro-5-hydroxycyclopentyl)acetamide.MS ESI calc'd. for C₁₄H₁₆ClF₂NO₂ [M+H]⁺ 304, found 304.

Step 8: To a stirred solution oftrans-N-benzyl-2-chloro-N-(2,2-difluoro-5-hydroxycyclopentyl)acetamide(750 mg, 2.46 mmol) in t-BuOH (20 mL) was added a 1M solution of KOtBuin THF (4.93 mL, 4.93 mmol) at 20° C. The reaction mixture was stirredat 20° C. for 2 hours and then the solvent was evaporated under reducedpressure. The residue was dissolved in EtOAc (20 mL), washed with brine(10 mL), dried over anhydrous Na₂SO₄, and concentrated under reducedpressure. Purification of the residue on a silica gel column (0 to 40%EtOAc/hexanes) afforded trans-4-benzyl-5,5-difluorohexahydrocyclopenta[b][1,4]oxazin-3(2H)-one. MS ESI calc'd. for C₁₄H₁₅F₂NO₂ [M+H]⁺ 268,found 268.

Step 9: LiAlH₄ (176 mg, 4.63 mmol) was added to a solution oftrans-4-benzyl-5,5-difluorohexahydrocyclopenta [b][1,4]oxazin-3(2H)-one(550 mg, 2.05 mmol) in THF (15 mL) at 0° C. The reaction mixture washeated at 70° C. for 2 hours and then cooled to room temperature. 5 mLof water was added slowly to quench the reaction and then the reactionwas extracted with EtOAc (100 mL). The organic layer was washed withbrine (50 mL), dried over anhydrous Na₂SO₄, and concentrated underreduced pressure. Purification of the residue on a silica gel column (0to 40% EtOAc/hexanes) affordedtrans-4-benzyl-5,5-difluorooctahydrocyclopenta[b][1,4]oxazine. MS ESIcalc'd. for C₁₄H₁₇F₂NO [M+H]⁺ 254, found 254.

Step 10: Trans-4-benzyl-5,5-difluorooctahydrocyclopenta[b][1,4]oxazine(350 mg, 1.38 mmol) was dissolved in MeOH (10 mL). 3M HCl in MeOH (1.5mL) was added and the solution was stirred for 1 hour. The solvent wasevaporated and further azeotroped using toluene. The residue was thendissolved in MeOH (10 mL), and 20% Pd(OH)₂/C (20% by wt, 50 mg) added.Hydrogen was purged through the reaction for 10 minutes and stirring wascontinued at room temperature under 1 atm of hydrogen for 16 hours. Thereaction was filtered through celite, and the filtrate was concentratedto afford trans-5,5-difluorooctahydrocyclopenta[b][1,4]oxazinehydrochloride. ¹H NMR (400 MHz, CD₃OD) δ4.16 (dd, J=13.6, 4.0 Hz, 1H),3.78-3.92 (m, 2H), 3.65 (m, 1H), 3.43 (dd, J=13.2, 2.4 Hz, 1H),3.28-3.31 (m, 2H), 2.15-2.55 (m, 2H), 1.89 (m, 1H). MS ESI calc'd. forC₇H₁₁F₂NO [M+H]⁺ 164, found 164.

Preparative Example 3.13trans-3-methyloctahydrocyclopenta[b][1,4]oxazine hydrochloride

Step 1: Cyclopentene oxide (5.0 g, 59.1 mmol), benzylamine (7.0 g, 65.3mmol) and titanium isopropoxide (3.40 g, 12.0 mmol) were taken in amicrowave vial and microwaved at 150° C. for 3 hours. The reactionmixture was then cooled and diluted with EtOAc (100 mL). The organiclayer was washed with water and dried over anhydrous Na₂SO₄. Evaporationof the solvent in vacuo and purification on a silica gel column (0 to20% MeOH/CH₂Cl₂) afforded trans-2-(benzylamino)cyclopentanol. MS APClcalc'd for C₁₂H₁₇NO [M+H]⁺ 192, found 192.

Step 2: To a suspension of NaH (6.0 g of 60% w/w in oil, 150 mmol) inTHF (300 mL) cooled at 0° C., trans-2-(benzylamino)cyclopentanol (9.6 g,50 mmol) was added slowly. After stirring for 15 minutes at 0° C., ethylbromoacetate (10 g, 60 mmol) was added slowly. The reaction mixture wasthen warmed to room temperature and stirred for 2 hours. Methanol (5.0mL) was added slowly to the reaction followed by addition of saturatedaqueous NH₄Cl (100 mL). The reaction mixture was then extracted withEtOAc (2×300 mL), and the combined organic layers were washed with water(100 mL) and dried over anhydrous Na₂SO₄. Evaporation of solvent invacuo followed by purification on a silica gel column (0 to 50%EtOAc/Hexanes) affordedtrans-4-benzylhexahydrocyclopenta[b][1,4]oxazin-3(2H)-one. MS APClcalc'd for C₁₄H₁₇NO₂ [M+H]⁺ 232, found 232.

Step 3: To -78° C. solution oftrans-4-benzylhexahydrocyclopenta[b][1,4]oxazin-3(2H)-one (5.0 g, 21.6mmol) in THF (200.0 mL), methyl lithium (11.0 mL of 3.00 M solution indimethoxyethane, 33.0 mmol) was added. The reaction mixture was slowlywarmed to 0° C. and stirred at that temperature for 2 hours. Acetic acid(2.00 mL, 2.00 g, 33.3 mmol) was added to the reaction dropwise at 0° C.and stirred for 10 minutes. Then BH₃ (33.0 mL, 1.0 M solution in THF,33.0 mmol) was added to the reaction at 0° C. and stirred for 30minutes. After slow addition of methanol (5.0 mL), saturated aqueousNH₄Cl (50.0 mL) solution was added. The reaction mixture was thenextracted with EtOAc (2×200 mL), and the combined organic layers werewashed with water (100 mL) and dried over anhydrous Na₂SO₄. Evaporationof solvent in vacuo and purification on a silica gel column (0 to 20%EtOAc/Hexanes) affordedtrans-4-benzyl-3-methyloctahydrocyclopenta[b][1,4]oxazine as a mixtureof diastereomers.

Step 4: To a solution oftrans-4-benzyl-3-methyloctahydrocyclopenta[b][1,4]oxazine (1.0 g, 4.3mmol) in methanol (20 mL), palladium hydroxide (50 mg of 10% w/w incarbon) was added. The reaction mixture was flushed with hydrogen andthen stirred under an atmosphere of hydrogen for two hours at roomtemperature. Aqueous HCl (2.0 mL of a 2.0 M solution) was added to thereaction, and the reaction mixture was filtered through a pad of celite,rinsing with MeOH. The filtrate was concentrated in vacuo to affordtrans-3-methyloctahydrocyclopenta[b][1,4]oxazine hydrochloride (mixtureof diastereomers).

Preparative Example 3.14 (2R,3R)-3-ethyl-2-methylmorpholinehydrochloride

Step 1: To a solution of (2R,3R)-3-aminopentan-2-ol hydrochloride (1.00g, 7.2 mmol) in DCM (20 mL) at rt was added sodium bicarbonate solution(604 mg, 7.2 mmol dissolved in 3.0 mL of water), dropwise. The reactionmixture was stirred for 1 hour, and the solvent was evaporated underreduced pressure. The residue and sodium cyanoborohydride (600 mg, 10.7mmol) were added to a solution of benzyaldehyde 877 mg, 8.6 mmol) in DCM(20 mL). The reaction mixture was stirred at room temperature overnightand then concentrated in vacuo. 30.0 mL water was added to this mixture,and the aqueous layer was extracted with dichloromethane (3×10 mL). Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. Purification of the residueon a silica gel column (0 to 50% EtOAc/hexanes) afforded(2R,3R)-3-(benzylamino)pentan-2-ol. MS APCl calc'd for C₁₂H₁₉NO [M+H]⁺194, found 194.

Step 2: Triethylamine (0.43 mL, 3.4 mmol) was added to a −40° C.solution of (2R,3R)-3-(benzylamino)pentan-2-ol (220 mg, 1.1 mmol) indichloromethane (100 mL), followed by the addition of 2-chloroacetylchloride (0.10 mL, 1.1 mmol) dropwise. The reaction mixture was stirredat −40° C. for 1 hour and then quenched with saturated NaHCO₃ solution.The layers were separated, and the aqueous layer was extracted withdichloromethane (3×10 mL).The combined organic layers were washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.Purification of the residue on a silica gel column (0 to 50%EtOAc/hexanes) affordedN-benzyl-2-chloro-N-((2R,3R)-2-hydroxypentan-3-yl)acetamide. MS APClcalc'd for C₁₄H₂₀ClNO₂ [M+H]⁺ 270, found 270.

Step 3: A solution ofN-benzyl-2-chloro-N-((2R,3R)-2-hydroxypentan-3-yl)acetamide (210 mg, 0.7mmol) in THF (5 mL) was added to a suspension of NaH (89 mg, 3.7 mmol)in THF (5 mL) at 0° C.The reaction mixture was stirred at 0° C. for 1hour and then quenched with saturated NH₄Cl solution. The layers wereseparated and the aqueous layer was extracted with EtOAc (2×10 mL). Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. Purification of the residueon a silica gel column (0 to 50% EtOAc/hexanes) afforded(5R,6R)-4-benzyl-5-ethyl-6-methylmorpholin-3-one. MS APCl calc'd forC₁₄H₁₉NO₂ [M+H]⁺ 234, found 234.

Step 4: LiAlH₄ (217 mg, 37.95 mmol) was added to a solution of(5R,6R)-4-benzyl-5-ethyl-6-methylmorpholin-3-one (200 mg, 0.85 mmol) inTHF (10 mL). The reaction mixture was heated at 70° C. for 3 hours andthen cooled to 0° C. At 0° C. was added aqueous sodium sulfate (15 mL).The mixture was stirred at room temperature for 10 minutes, and thewhite solid was removed by filtration. The filtrate was extracted withEtOAc (3×15 mL), dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo. Purification of the residue on a silica gel column (0 to 30%EtOAc/hexanes) afforded (2R,3R)-4-benzyl-3-ethyl-2-methylmorpholine. MSAPCl calc'd for C₁₄H₂₁ NO [M+H]⁺ 220, found 220.

Step 5: Pd(OH)₂ (15.0 mg, 10% on carbon) was added to a solution of(2R,3R)-4-benzyl-3-ethyl-2-methylmorpholine (110 mg, 0.50 mmol) in MeOH(10 mL) under N₂. Hydrogen was bubbled through the reaction mixture forone minute and then the reaction was stirred at rt under hydrogen (1atm) for 2 hours. Then, N₂ was bubbled through the reaction for 1minute. A solution of HCl (3M, 3 mL, 9 mmol) in methanol was added. Thereaction mixture was stirred at room temperature for 30 minutes andconcentrated in vacuo to afford (2R,3R)-3-ethyl-2-methylmorpholinehydrochloride. ¹H NMR (300 MHz, DMSO-d₆) δ 9.45-9.34 (br s, 1H),3.84-3.91 (m, 1H), 3.68-3.78 (m, 1H), 3.53-3.61 (m, 1H), 3.08-3.21 (m,1H), 2.93-3.01 (m, 1H), 2.70-2.85 (m, 1H), 1.45-1.81 (m, 2H), 1.13 (d,J=6.3 Hz, 3H), 0.90-1.05 (m, 3H). MS APCl calc'd for C₇H₁₅NO [M+H]⁺ 130,found 130.

Preparative Example 3.15(trans)-6,6-difluorooctahydrocyclopenta[b][1,4]oxazine (racemic HClsalt)

Step 1: To a solution of cyclopent-3-enol (500 mg, 6.0 mmol) in CH₂Cl₂(30 mL) at 0° C. was added imidazole (1.06 g, 15.6 mmol) and TBDPS-Cl(2.1 g, 7.8 mmol). The reaction was gradually warmed to room temperatureand stirred for 16 hours. The reaction was then diluted with water (40mL) and extracted using EtOAc (100 mL). The organic layer was separated,washed with brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated in vacuo. Purification of the residue on a silica gelcolumn with 0 to 5% EtOAc/Hexanes affordedtert-butyl(cyclopent-3-en-1-yloxy)diphenylsilane, which was thendissolved in CH₂Cl₂ (30 mL). 70% m-CPBA (830 mg, 6.9 mmol) was added at0° C. The reaction was gradually warmed to room temperature whilestirring for 16 hours. The reaction was then diluted with a saturatedaqueous solution of NaHCO₃ (40 mL) and extracted using CH₂Cl₂ (100 mL).The organic layer was separated, washed with brine, dried over anhydrousNa₂SO₄, filtered, and concentrated in vacuo. Purification of the residueon a silica gel column with 0 to 20% EtOAc/Hexanes afforded(6-oxabicyclo[3.1.0]hexan-3-yloxy)(tert-butyl)diphenylsilane.

Step 2: Ti(OiPr)₄ (100 mg, 0.35 mmol) was added to a solution of(6-oxabicyclo[3.1.0]hexan-3-yloxy)(tert-butyl)diphenylsilane (1.0 g, 3.0mmol) in benzylamine (1.5 mL). The mixture was heated in a microwave at130° C. for 3 h and then cooled to room temperature. 16 mL of MeOH/water(1:8) was added to the reaction, and the mixture was stirred for 10minutes. The gummy precipitate that formed was filtered off, and thissolid was dissolved in acetonitrile (30 mL). The solution was filteredagain, and the filtrate was evaporated to dryness. The residue wasloaded onto a C-18 column and purified using 0-100% CH₃CN/water toafford(trans)-2-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)cyclopentanol.MS APCl calc'd for C₂₈H₃₅NO₂Si [M+H]⁺ 446, found 446.5tep 3:Triethylamine (0.90 mL, 6.42 mmol) was added to a solution of(trans)-2-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)cyclopentanol(950 mg, 2.1 mmol) in dichloromethane (10 mL) at −40° C., followed bydropwise addition of 2-chloroacetyl chloride (264 mg, 2.3 mmol) to thereaction. The reacton mixture was stirred at −40° C. for 1 hour and wasquenched with saturated aqueous NaHCO₃ solution. The layers wereseparated and the aqueous layer was extracted with dichloromethane (3×20mL). The combined organic layers were washed with brine, dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo. Purification ofthe residue on a silica gel column (0 to 20% EtOAc/hexanes) afforded(trans)-N-benzyl-N-(4-((tert-butyldiphenylsilyl)oxy)-2-hydroxycyclopentyl)-2-chloroacetamide.

Step 4: To a solution of(trans)-N-benzyl-N-(4-((tert-butyldiphenylsilyl)oxy)-2-hydroxycyclopentyl)-2-chloroacetamide(260 mg, 0.5 mmol) in t-BuOH (5 mL) was added a solution of KOtBu (0.75mL, 0.75 mmol) in THF (10 mL) at 15° C. The reaction mixture was stirredat 15° C. for 1 hour and then the solvent was evaporated under reducedpressure. The residue was dissolved in EtOAc (20 mL), washed with brine(10 mL), dried over anhydrous Na₂SO₄, and concentrated under reducedpressure. Purification of the residue on a C-18 column (0 to 100%CH₃CN/water) afforded(trans)-4-benzyl-6-((tert-butyldiphenylsilyl)oxy)hexahydrocyclopenta[b][1,4]oxazin-3(2H)-one.

Step 5: LiAlH₄ (176 mg, 4.63 mmol) was added to a solution of(trans)-4-benzyl-6-((tert-butyldiphenylsilypoxy)hexahydrocyclopenta[b][1,4]oxazin-3(2H)-one(48 mg, 0.1 mmol) in THF (1.0 mL). The reaction mixture was heated at70° C. for 2 hours and then cooled to room temperature. Water was addedto quench the reaction. The reaction mixture was stirred at roomtemperature for 15 minutes, and the white solids were removed byfiltration. The filtrate was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. Purification of the residue on a silica gelcolumn (0 to 50% EtOAc/hexanes) afforded(trans)-4-benzyl-6-((tert-butyldiphenylsilyl)oxy)octahydrocyclopenta[b][1,4]oxazine. MS APCl calc'd for C₃₀H₃₇NO₂Si [M+H]⁺ 472, found 472.

Step 6:(Trans)-4-benzyl-6-((tert-butyldiphenylsilyl)oxy)octahydrocyclopenta[b][1,4]oxazine (1.0 g, 2.1 mmol) was suspended in 3M HCl in MeOH (8.0mL) and heated in a sealed tube at 45° C. for 16 hours. Solid NaHCO₃ wasadded to the reaction until the pH was neutral. Solids were filtered offand the solvent was evaporated under reduced pressure. Purification ofthe residue on a silica gel column with 0 to 20% MeOH/CH₂Cl₂ afforded(trans)-4-benzyloctahydrocyclopenta[b][1,4]oxazin-6-ol, which wasdissolved in anhydrous CH₂Cl₂ (20 mL). The solution was cooled to 0° C.and Dess-Martin periodinane (1.40 g, 3.2 mmol) was added in severalportions. The reaction was warmed to 10° C. over 2 hours and thenquenched by adding a mixture (1:1) of saturated aqueous NaHCO₃ andNa₂S₂O₃ solution. The layers were separated, and the aqueous layer wasextracted using CH₂Cl₂ (20 mL). The combined organics were dried overNa₂SO₄, filtered, and concentrated under reduced pressure. Purificationof the residue on a silica gel column with 0 to 20% MeOH/CH₂Cl₂ afforded(trans)-4-benzylhexahydrocyclo penta[b][1,4]oxazin-6(2H)-one. MS APClcalc'd for C₁₄H₁₇NO₂ [M+H]⁺ 232, found 232.

Step 7: (trans)-4-benzylhexahydrocyclo penta[b][1,4]oxazin-6(2H)-one(150 mg, 0.64 mmol) was dissolved in toluene (3.0 mL) and DAST (522 mg,3.2 mmol) was added dropwise. The reaction was then heated at 90° C. for2 hours, cooled to 0° C., and quenched by adding saturated aqueousNaHCO₃ solution (2 mL). The layers were separated and the aqueous layerwas extracted using CH₂Cl₂ (10 mL). The combined organics wereconcentrated under reduced pressure. Purification of the residue on asilica gel column with 0 to 60% EtOAc/hexanes afforded(trans)-4-benzyl-6,6-difluorooctahydrocyclopenta[b][1,4]oxazine, whichwas then dissolved in MeOH (2 mL). 3M HCl in MeOH (0.3 mL) was added tothe above solution and it was stirred for 1 hour. The solvent wasevaporated and the residue was further azeotroped using toluene. Theresidue was then dissolved in MeOH (2.0 mL) and Pd(OH)₂/C (8.0 mg) wasadded. Hydrogen was purged through the reaction for 10 minutes and thenthe reaction was stirred at room temperature under 1 atm of hydrogen for16 hours. The reaction was filtered through celite, and the filtrate wasconcentrated to afford(trans)-6,6-difluorooctahydrocyclopenta[b][1,4]oxazine hydrochloride(racemic). MS APCl calc'd for C₇H₁₁F₂NO [M+H]⁺ 164, found 164.

Preparative Example 3.16(trans)-6-fluorooctahydrocyclopenta[b][1,4]oxazine (HCl salt)

Step 1: (trans)-4-benzyloctahydrocyclopenta[b][1,4]oxazin-6-ol(Intermediate 3.15, Step 6) (250 mg, 1.07 mmol) was dissolved in CH₂Cl₂(10 mL), and DAST (518 mg, 3.2 mmol) was added dropwise. The reactionwas stirred for 3 hours and quenched by adding saturated aqueous NaHCO₃(15 mL). The layers were separated, and the aqueous layer was extractedusing CH₂Cl₂ (2×20 mL). The combined organic layers were dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue waspurified on a silica gel column (0 to 50% EtOAc/hexanes) to afford aslower eluting and a faster eluting diastereomer (both racemic) of(trans)-4-benzyl-6-fluorooctahydrocyclopenta[b][1,4]oxazine. Fastereluting diastereomer: ¹H NMR (400 MHz, CDCl₃) δ 7.21-7.35 (m, 5H), 5.11(m, 1H), 3.80-3.89 (m, 2H), 3.64-3.75 (m, 2H), 3.11 (d, J=13.2 Hz, 1H),2.63 (m, 1H), 2.52 (m, 1H), 2.23 (m, 1H), 0.57-2.21 (m, 4H). MS APClcalc'd for C₁₄H₁₈FNO [M+H]⁺ 236, found 236. Slower eluting diastereomer:¹H NMR (400 MHz, CDCl₃) δ 7.22-7.33 (m, 5H), 5.09 (m, 1H), 3.80-3.91 (m,2H), 3.66 (m, 1H), 3.27 (m, 1H), 3.20 (d, J=12.8 Hz, 1H), 2.48-3.15 (m,4H), 2.15 (m, 1H), 1.88 (m, 1H), 1.60 (m, 1H). MS APCl calc'd forC₁₄H₁₈FNO [M+H]⁺ 236, found 236.

Step 2: (Trans)-4-benzyl-6-fluorooctahydrocyclopenta[b][1,4]oxazine

(racemic faster eluting diastereomer) (200 mg, 0.85 mmol) was dissolvedin MeOH (10 mL). 3M HCl in MeOH (1.5 mL) was added, and the solution wasstirred for 1 hour. The solvent was evaporated, and the residue wasfurther azeotroped using toluene. The residue was then dissolved in MeOH(10 mL), and 20% Pd(OH)₂/C (20% by wt, 40 mg) was added. Hydrogen waspurged through the reaction for 10 minutes, and then the reaction wasstirred at room temperature under 1 atm of hydrogen for 16 hours. Thereaction was filtered through celite, and the filtrate was concentratedto afford (trans)-6-fluorooctahydrocyclopenta[b][1,4]oxazinehydrochloride (racemic, diastereomer 1). MS ES calc'd for C₇H₁₂FNO[M+H]⁺ 146, found 146. A similar procedure was carried out starting fromthe slower eluting diastereomer of step 1 to produce a second racemicdiastereomer of product.

Preparative Intermediate 3.17(trans)-hexahydro-2H-furo[3,4-b][1,4]oxazine (HCl salt, racemic)

Step 1: Ti(O^(i)Pr)₄ (1.0 mL, 3.48 mmol) was added to a solution of3,6-dioxabicyclo[3.1.0]hexane (1.5 g, 17.4 mmol) in benzylamine (2.0mL). The mixture was irradiated in a microwave reactor at 130° C. for 2hours. It was cooled to room temperature, and 50 mL of saturated aqueousNH₄Cl solution and 20 mL of EtOAc were added to the reaction. Themixture was stirred for 10 minutes. The resulting gummy precipitate wasfiltered over a celite bed, and the filtrate was extracted using EtOAc(100 mL). The organic layer was separated, washed with brine, dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue waspurified by reverse phase chromatography on a C-18 column (0-100%CH₃CN/water) to afford trans-4-(benzylamino) tetrahydrofuran-3-ol. MSAPCl calc'd for C₁₁H₁₅NO₂ [M+H]⁺ 194, found 194.

Step 2: To a solution of trans-4-(benzylamino)tetrahydrofuran-3-ol (4.1g, 21.2 mmol) in CH₂Cl₂ (40 mL) at −40° C. was added triethylamine (5.9mL, 42.4 mmol) followed by dropwise addition of 2-chloroacetyl chloride(1.6 mL, 21.2 mmol). The reaction was stirred at −40° C. for 2 hours.The reaction was quenched with saturated aqueous NaHCO₃ (40 mL) andextracted using CH₂Cl₂ (100 mL). The organic layer was separated, washedwith brine, dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo. Purification of the residue on a silica gel column with 0 to 100%EtOAc/hexanes affordedtrans-N-benzyl-2-chloro-N-(4-hydroxytetrahydrofuran-3-yl)acetamide. MSAPCl calc'd for C₁₃H₁₆ClNO₃ [M+H]⁺ 270, found 270.

Step 3: To a solution oftrans-N-benzyl-2-chloro-N-(4-hydroxytetrahydrofuran-3-yl)acetamide (4.7g, 17.4 mmol) in t-BuOH (40 mL) was added KOt-Bu (1.0 M in THF; 34.8 mL,34.8 mmol) solution at 25° C. The reaction mixture was stirred at 25° C.for 2 hours and then the solvent was evaporated under reduced pressure.The residue was dissolved in water and extracted with EtOAc (100 mL).The organic extract was washed with brine (40 mL), dried over anhydrousNa₂SO₄, and concentrated under reduced pressure to affordtrans-4-benzyltetrahydro-2H-furo[3,4-b][1,4]oxazin-3(4H)-one. MS APClcalc'd for C₁₃H₁₅NO₃ [M+H]⁺ 234, found 234.

Step 4: To a solution oftrans-4-benzyltetrahydro-2H-furo[3,4-b][1,4]oxazin-3(4H)-one (3.1 g,13.2 mmol) in THF (35 mL) at 0° C. was added BH₃:THF (1.0 M in THF; 39.7mL, 39.7 mmol). The reaction mixture was stirred at 0° C. for 16 hours.The reaction was quenched with aqueous 1 N NaOH solution, adjusting topH 13, and extracted with EtOAc (100 mL). The organic extract was washedwith brine (40 mL), dried over anhydrous Na₂SO₄, and concentrated underreduced pressure to affordtrans-4-benzylhexahydro-2H-furo[3,4-b][1,4]oxazine. ¹H NMR (400 MHz,CDCl₃) δ 7.29-7.31 (m, 5H), 3.96 (t, J=7.2 Hz, 1H), 3.92 (ddd, J=11.6,3.6, 1.2 Hz, 1H), 3.86 (m, 1H), 3.67-3.77 (m, 2H), 3.52-3.66 (m, 3H),3.45 (dd, J=12.0, 9.0 Hz, 1H), 3.34 (d, J=13.2 Hz, 1H), 2.71 (ddd,J=12.0, 2.8, 1.2 Hz, 1H), 2.42 (ddd, J=15.6, 8.8, 6.8 Hz, 1H). MS APClcalc'd for C₁₃H₁₇NO₂ [M+H]⁺ 220, found 220.

Step 5: To a solution oftrans-4-benzylhexahydro-2H-furo[3,4-b][1,4]oxazine (600 mg, 2.73 mmol)in MeOH (10 mL) at room temperature was added Pd(OH)₂/C (250 mg).Hydrogen was purged through the reaction for 10 minutes and then thereaction was stirred at room temperature under 1 atm of hydrogen for 2hours. Concentrated HCl (0.3 mL) was added, and the solution was stirredfor 15 minutes. The reaction was filtered through celite, and thesolvent was evaporated to afford(trans)-hexahydro-2H-furo[3,4-b][1,4]oxazine (HCl salt, racemic). ¹H NMR(400 MHz, CD₃OD) δ 3.72-4.29 (m, 6H), 3.41-3.69 (m, 3H), 3.23-3.35 (m,1H).

Preparative Example 3.18(trans)-2-methyloctahydrocyclopenta[b][1,4]oxazine (HCl salt) (mixtureof diastereomers)

mixture of diastereomers(Trans)-2-methyloctahydrocyclopenta[b][1,4]oxazine (HCl salt) (mixtureof diastereomers) was prepared using chemistry similar to that describedfor Preparative Example 3.17. In step 1,3,6-dioxabicyclo[3.1.0]hexanewas replaced with cyclopentene oxide, and in step 2,2-chloroacetylchloride was replaced with 2-chloropropanoyl chloride.

Example 3.13-{4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one

Step 1: To a vial was added2-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Preparative Example 3.1, 382.2 mg, 0.86 mmol),(S)-2-(fluoromethyl)pyrrolidine hydrochloride (240 mg, 1.72 mmol),potassium fluoride (250 mg, 4.30 mmol), DMSO (2.6 mL), andN,N-diisopropylethylamine (0.75 mL, 4.30 mmol). The vial was sealed andheated to 100° C. for 16 hours. The reaction mixture was cooled to roomtemperature, diluted with ethyl acetate, and washed with water and thenbrine. The organic layer was dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (0-100% ethyl acetate/hexanes, linear gradient) toafford4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ESI calc'd. for C₂₅H₂₈ClFN₆ [M+H]⁺ 467, found 467.

Step 2: Hydroxylamine hydrochloride (108 mg, 1.56 mmol), sodiumbicarbonate (196 mg, 2.34 mmol), and water (1.56 mL) were combined in avial and stirred for 15 minutes. This solution was added to a vialcontaining4-[5-chloropyridin-3-yl)-2-(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(364 mg, 0.78 mmol) dissolved in ethanol (3.6 mL). The mixture wassealed and heated at 100° C. for 1 hour. The reaction was cooled to roomtemperature, quenched with water, and extracted with ethyl acetate (2×).The combined organic layers were dried over sodium sulfate, filtered,and concentrated to afford4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide.MS ESI calc'd. for C₂₅H₃₁ClFN₇O [M+H]⁺ 500, found 500.

Step 3: To a solution of4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide(408 mg, 0.82 mmol) and 1,1′-carbonyldiimidazole (146 mg, 0.90 mmol)dissolved in acetonitrile (8.2 mL) was added1,8-diazabicyclo[5.4.0]undec-7-ene (0.488 mL, 3.26 mmol). The reactionmixture was stirred at room temperature for 1 hour. The reaction waswashed with water and extracted with dichloromethane. The organic layerwas dried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by silica gel chromatography (0-100%ethyl acetate/hexanes, linear gradient) to afford3-{4-[5-chloropyridin-3-yl)-2-(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one.MS ESI calc'd. for C₂₆H₂₉ClFN₇O₂ [M+H]⁺ 526, found 526. ¹H NMR (500 MHz,DMSO-d₆) δ 12.83 (s, 1H), 8.93 (s, 1H), 8.78 (s, 1H), 8.48 (s, 1H), 7.83(s, 1H), 4.67-4.42 (m, 3H), 3.91-3.81 (m, 1H), 3.79-3.64 (m, 2H),3.53-3.45 (m, 1H), 2.20-2.12 (broad, 1H), 2.06-1.98 (broad, 1H),1.94-1.78 (m, 2H), 1.40-1.31 (broad, 2H), 1.17-1.07 (broad, 1H),1.06-0.96 (broad, 1H), 0.89 (d, J=12.5, 1H), 0.67 (d, J=6.4, 3H),0.63-0.36 (m, 5H).

Example 3.23-{4-(5-chloropyridin-3-yl)-2-(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one

Step 1: To octahydrocyclopenta[b][1,4]oxazine hydrochloride (purchasedfrom Enamine) (300 mg, 1.83 mmol) dissolved in dichloromethane (2.4 mL)was added benzyl chloroformate (0.44 mL, 2.57 mmol). Triethylamine (0.72mL, 5.13 mmol) was added slowly to the reaction mixture, and thereaction was stirred for 16 hours at room temperature. The mixture wasquenched with saturated aqueous sodium bicarbonate and extracted withdichloromethane (2×). The combined organic layers were dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel chromatography (0-100% ethyl acetate/hexanes,linear gradient), and then purified by chiral supercritical fluidchromatography (Chiralpak AZ-H, 21×250 mm, 10% methanol in CO₂) toafford the trans stereoisomers of benzylhexahydrocyclopenta[b][1,4]oxazine-4(4aH)-carboxylate. (4aS,7aS)-Benzylhexahydrocyclopenta[b][1,4]oxazine-4(4aH)-carboxylate (faster elutingenantiomer): MS ESI calc'd. for C₁₅H₁₉NO₃ [M+H]⁺ 262, found 262;(4aR,7aR)-Benzyl hexahydrocyclopenta[b][1,4]oxazine-4(4aH)-carboxylate(slower eluting enantiomer): MS ESI calc'd. for C₁₅H₁₉NO₃ [M+H]⁺ 262,found 262.

Step 2: To (4aR,7aR)-benzylhexahydrocyclopenta[b][1,4]oxazine-4(4aH)-carboxylate (199.5 mg, 0.76mmol) dissolved in ethyl acetate (5 mL) was added palladium (10 weight %on carbon, 81 mg, 0.076 mmol). Added hydrogen gas via balloon, and thereaction was stirred under a hydrogen atmosphere for two hours at roomtemperature. The mixture was filtered over celite and concentrated underreduced pressure to afford (4aR,7aR)-octahydrocyclopenta[b][1,4]oxazine.¹H NMR (500 MHz, CDCl₃) δ 3.90 (d, J=11.5, 1H), 3.64 (t, J=11.6, 1H),3.17 (dd, J=9.2, 18.3, 1H), 2.96 (t, J=11.9, 1H), 2.88 (d, J=12.2, 1H),2.59-2.47 (m, 1H), 1.89 (dd, J=9.1, 18.4, 1H), 1.84-1.61 (m, 4H),1.57-1.44 (m, 1H), 1.38-1.26 (m, 1H).

Step 3: To a vial was added2-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Preparative Example 3.1, 90 mg, 0.202 mmol),(4aR,7aR)-octahydrocyclopenta[b][1,4]oxazine (51.5 mg, 0.405 mmol),potassium fluoride (58.8 mg, 1.01 mmol), DMSO (0.62 mL), andN,N-diisopropylethylamine (0.18 mL, 1.01 mmol). The vial was sealed andheated to 100° C. for 16 hours. The reaction mixture was cooled to roomtemperature, diluted with ethyl acetate, and washed with water and thenbrine. The organic layer was dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (0-100% ethyl acetate/hexanes, linear gradient) toafford4-(5-chloropyridin-3-yl)-2-((4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ESI calc'd. for C₂₇H₃₁ClN₆O [M+H]⁺ 491, found 491.

Step 4: Hydroxylamine hydrochloride (24.3 mg, 0.35 mmol), sodiumbicarbonate (44 mg, 0.52 mmol), and water (0.52 mL) were combined in avial and stirred for 15 minutes. This solution was added to a vialcontaining4-(5-chloropyridin-3-yl)-2-((4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(85.8 mg, 0.175 mmol) dissolved in ethanol (1.2 mL). The mixture wassealed and heated at 100° C. for 1 hour. The reaction was cooled to roomtemperature, quenched with water, and extracted with ethyl acetate (2×).The combined organic layers were dried over sodium sulfate, filtered,and concentrated to afford4-(5-chloropyridin-3-yl)-2-((4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide.MS ESI calc'd. for C₂₇H₃₄ClN₇O₂ [M+H]⁺ 524, found 524.

Step 5: To a solution of4-(5-chloropyridin-3-yl)-2-((4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide(86.7 mg, 0.165 mmol) and 1,1′-carbonyldiimidazole (29.5 mg, 0.18 mmol)dissolved in acetonitrile (1.1 mL) was added1,8-diazabicyclo[5.4.0]undec-7-ene (0.099 mL, 0.66 mmol). The reactionmixture was stirred at room temperature for 1 hour. The reaction waswashed with water and extracted with dichloromethane. The organic layerwas dried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by silica gel chromatography (0-10%methanol/dichloromethane, and then 0-100% ethyl acetate/hexanes, lineargradient) to afford3-{4-(5-chloropyridin-3-yl)-2-(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one.MS ESI calc'd. for C₂₈H₃₂ClN₇O₃ [M+H]⁺ 550, found 550. ¹H NMR (500 MHz,DMSO-d₆) δ 12.89 (s, 1H), 8.93 (s, 1H), 8.82 (s, 1H), 8.46 (s, 1H), 8.07(s, 1H), 3.96 (d, J=10.8, 1H), 3.92-3.78 (m, 2H), 3.62 (d, J=14.4, 1H),3.56 (d, J=12.8, 1H), 3.44-3.35 (m, 1H), 3.07-2.98 (m, 1H), 2.89-2.79(m, 1H), 2.33-2.24 (m, 1H), 1.92-1.82 (m, 1H), 1.77-1.49 (m, 3H), 1.40(d, J=12.8, 1H), 1.34 (d, J=12.7, 1H), 1.19-0.95 (m, 2H), 0.89-0.78 (m,1H), 0.77-0.69 (m, 2H), 0.67 (d, J=6.4, 3H), 0.65-0.60 (m, 1H), 0.50 (d,J=11.6, 1H), 0.44-0.31 (m, 2H).

Example 3.33-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one

Step 1: To a vial was added2-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Preparative Example 3.1, 350 mg, 0.79 mmol),(S)-2-(trifluoromethyl)pyrrolidine (purchased from Sigma Aldrich) (219mg, 1.57 mmol), potassium fluoride (229 mg, 3.93 mmol), DMSO (2.4 mL),and N,N-diisopropylethylamine (0.69 mL, 3.93 mmol). The vial was sealedand heated to 100° C. for 16 hours. The reaction mixture was cooled toroom temperature, diluted with ethyl acetate, and washed with water andthen brine. The organic layer was dried over sodium sulfate, filtered,and concentrated under reduced pressure. The residue was purified bysilica gel chromatography (0-100% ethyl acetate/hexanes, lineargradient) to afford4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ESI calc'd. for C₂₅H₂₆ClF₃N₆ [M+H]⁺ 503, found 503.

Step 2: Hydroxylamine hydrochloride (44.5 mg, 0.64 mmol), sodiumbicarbonate (81 mg, 0.96 mmol), and water (0.64 mL) were combined in avial and stirred for 15 minutes. This solution was added to a vialcontaining4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(161 mg, 0.32 mmol) dissolved in ethanol (1.5 mL). The mixture wassealed and heated at 100° C. for 1 hour. The reaction was cooled to roomtemperature, quenched with water, and extracted with ethyl acetate (2×).The combined organic layers were dried over sodium sulfate, filtered,and concentrated to afford4-(5-chloropyridin-3-yl)-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide.MS ESI calc'd. for C₂₅H₂₉ClF₃N₇O [M+H]⁺ 536, found 536.

Step 3: To a solution of4-(5-chloropyridin-3-yl)-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide(169 mg, 0.315 mmol) and 1,1′-carbonyldiimidazole (56.2 mg, 0.35 mmol)dissolved in acetonitrile (3.2 mL) was added1,8-diazabicyclo[5.4.0]undec-7-ene (0.188 mL, 1.26 mmol). The reactionmixture was stirred at room temperature for 1 hour. The reaction waswashed with water and extracted with dichloromethane. The organic layerwas dried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by silica gel chromatography (0-100%ethyl acetate/hexanes, linear gradient) to afford3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one.MS ESI calc'd. for C₂₆H₂₇ClF₃N₇O₂ [M+H]⁺ 562, found 562. ¹H NMR (500MHz, DMSO-d₆) δ 12.87 (s, 1H), 8.95 (s, 1H), 8.80 (s, 1H), 8.49 (s, 1H),7.94 (s, 1H), 5.40-5.31 (m, 1H), 3.95-3.85 (m, 1H), 3.80-3.72 (m, 2H),3.59-3.51 (m, 1H), 2.44-2.33 (m, 1H), 2.11-1.95 (m, 2H), 1.95-1.83 (m,1H), 1.42-1.32 (broad, 2H), 1.11-0.98 (broad, 2H), 0.89 (d, J=12.1, 1H),0.67 (d, J=6.3, 3H), 0.65-0.53 (m, 2H), 0.53-0.34 (m, 3H). Example 3.90

3-{4-(5-chloropyridin-3-yl)-2-[(2S,4R)-4-methoxy-2-(propan-2-yl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one

Step 1: To a vial was added2-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(150 mg, 0.337 mmol), (3R,5S)-5-(propan-2-yl)pyrrolidin-3-ol(TFA salt,164 mg, 0.675 mmol), potassium fluoride (98 mg, 1.68 mmol), DMSO (1 mL),and N,N-diisopropylethylamine (0.589 mL, 3.37 mmol). The vial was sealedand heated to 100° C. for 16 hours. The reaction mixture was cooled toroom temperature, diluted with ethyl acetate, and washed with water andthen brine. The organic layer was dried over sodium sulfate, filtered,and concentrated under reduced pressure. The residue was purified bysilica gel chromatography (0-100% ethyl acetate/hexanes, lineargradient) to afford4-(5-chloropyridin-3-yl)-2-[(2S,4R)-4-hydroxy-2-(propan-2-yl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ESI calc'd. for C₂₇H₃₃ClN₆O [M+H]⁺ 493, found 493.

Step 2: To a mixture of4-(5-chloropyridin-3-yl)-2-[(2S,4R)-4-hydroxy-2-(propan-2-yl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(71.4 mg, 0.145 mmol) in THF (0.483 mL) at 0° C. was added methyl iodide(31.1 μl, 0.498 mmol) followed by sodium hydride (7.65 mg, 0.319 mmol).The mixture was stirred for 3 hours at room temperature, quenched withice, and diluted with dichloromethane. The organic layer was washed withwater and brine, dried over sodium sulfate, filtered, and concentratedto afford4-(5-chloropyridin-3-yl)-2-[(2S,4R)-4-methoxy-2-(propan-2-yl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ESI calc'd. for C₂₈H₃₆ClN₆O [M+H]⁺ 507, found 507.

Step 3: Hydroxylamine hydrochloride (20.2 mg, 0.29 mmol), sodiumbicarbonate (36.6 mg, 0.44 mmol), and water (0.436 mL) were combined ina vial and stirred for 15 minutes. This solution was added to a vialcontaining4-(5-chloropyridin-3-yl)-2-[(2S,4R)-4-methoxy-2-(propan-2-yl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(73.7 mg, 0.145 mmol) dissolved in ethanol (1 mL). The mixture wassealed and heated at 100° C. for 1 hour. The reaction was cooled to roomtemperature, quenched with water, and extracted with ethyl acetate (2×).The combined organic layers were dried over sodium sulfate, filtered,and concentrated to afford4-(5-chloropyridin-3-yl)-N′-hydroxy-2-[(2S,4R)-4-methoxy-2-(propan-2-yl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide.MS ESI calc'd. for C₂₈H₃₈ClN₇O₂ [M+H]⁺ 540, found 540.

Step 4: To a solution of4-(5-chloropyridin-3-yl)-N′-hydroxy-2-[(2S,4R)-4-methoxy-2-(propan-2-yl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide(79 mg, 0.146 mmol) and 1,1′-carbonyldiimidazole (26.1 mg, 0.161 mmol)dissolved in acetonitrile (1 mL) was added1,8-diazabicyclo[5.4.0]undec-7-ene (0.087 mL, 0.585 mmol). The reactionmixture was stirred at room temperature for 1 hour. The reaction waswashed with water and extracted with dichloromethane. The organic layerwas dried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by silica gel chromatography (0-10%methanol/dichloromethane, and then 0-100% ethyl acetate/hexanes, lineargradient) to afford3-{4-(5-chloropyridin-3-yl)-2-[(2S,4R)-4-methoxy-2-(propan-2-yl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one.MS ESI calc'd. for C₂₉H₃₆ClN₇O₃ [M+H]⁺ 566, found 566. ¹H NMR (500 MHz,DMSO-d₆) δ 12.82 (s, 1H), 8.96 (d, J=1.8, 1H), 8.78 (d, J=2.4, 1H), 8.50(t, J=2.1, 1H), 7.82 (s, 1H), 4.39-4.34 (m, 1H), 3.98 (s, 1H), 3.85-3.81(m, 1H), 3.77 (s, 2H), 3.53 (dd, J=5.9, 15.1, 1H), 3.20 (s, 3H),2.31-2.27 (m, 1H), 2.09-2.00 (m, 1H), 1.80-1.72 (m, 1H), 1.37 (d,J=10.5, 2H), 1.12-1.05 (m, 1H), 1.05-0.96 (m, 1H), 0.89 (d, J=7.0, 3H),0.87 (s, 1H), 0.76 (d, J=6.8, 3H), 0.6 (d, J=6.5, 3H), 0.61-0.55 (m,1H), 0.54-0.48 (m, 1H), 0.48-0.44 (m, 1H), 0.40-0.34 (m, 2H).

Example 3.913-{4-(5-chloropyridin-3-yl)-2-[(2S,4R)-4-hydroxy-2-(propan-2-yl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one

Using a procedure analogous to that described in Example 3.90 (Step 3and Step 4), and starting with4-(5-chloropyridin-3-yl)-2-[(2S,4R)-4-hydroxy-2-(propan-2-yl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(product in Step 1, Example 3.90),3-{4-(5-chloropyridin-3-yl)-2-[(2S,4R)-4-hydroxy-2-(propan-2-yl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-onewas prepared. MS ESI calc'd. for C₂₈H₃₄ClN₇O₃ [M+H]⁺ 552, found 552. ¹HNMR (500 MHz, DMSO-d₆) δ 12.81 (s, 1H), 8.92 (d, J=1.8, 1H), 8.77 (d,J=2.4, 1H), 8.47 (t, J=2.1, 1H), 7.82 (s, 1H), 4.90 (d, J=2.5, 1H),4.52-4.46 (m, 1H), 4.33 (s, 1H), 3.85-3.73 (m, 2H), 3.56 (d, J=10.4,1H), 3.48 (dd, J=5.8, 14.9, 1H), 2.36-2.26 (m, 1H), 1.88-1.74 (m, 2H),1.36 (d, J=10.5, 2H), 1.16-1.05 (m, 1H), 1.05-0.95 (m, 1H), 0.89 (d,J=6.9, 3H), 0.86-0.79 (m, 1H), 0.75 (d, J=6.8, 3H), 0.66 (d, J=6.5, 3H),0.64-0.54 (m, 1H), 0.53-0.49 (m, 1H), 0.49-0.41 (m, 1H), 0.41-0.32 (m,2H).

Example 3.943-(4-(5-chloropyridin-3-yl)-2-(methyl(2,2,2-trifluoroethyl)amino)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one

Step 1: To a sealed reaction vessel was added cesium fluoride (0.085 g,0.56 mmol). The reaction vessel was heated to 150° C. for 3 hours withstirring, under high vacuum. The vial was cooled to ambient temperatureunder high vacuum. The reaction vessel was backfilled with argon, andnext was added a solution of 2,2,2-trifluoro-N-methylethanamine(purchased from Enamine) (0.019 g, 0.17 mmol) and2-bromo-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Preparative Example 3.1, 0.025 g, 0.056 mmol) in DMSO (0.30 mL). Thereaction was heated to 100° C. for 12 hours. The reaction was cooled,diluted with H₂O (2.0 mL) and extracted with EtOAc (2×5.0 mL). Thecombined organics were dried over anhydrous MgSO₄, filtered andconcentrated in vacuo to afford4-(5-chloropyridin-3-yl)-2-(methyl(2,2,2-trifluoroethyl)amino)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrileas a crude residue. MS ESI calc'd. for C₂₃H₂₄ClF₃N₆ [M+H]⁺ 477, found477.

Step 2: To a reaction vessel containing the residue of4-(5-chloropyridin-3-yl)-2-(methyl(2,2,2-trifluoroethypamino)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile(0.027 g, 0.056 mmol) suspended in EtOH (1.0 mL) was added hydroxylamine(0.10 mL, 50% w/w in H₂O). The reaction was stirred at ambienttemperature for 3 hours. To the reaction was then added benzene (2.0mL), and the reaction was concentrated in vacuo to afford4-(5-chloropyridin-3-yl)-N-hydroxy-2-(methyl(2,2,2-trifluoroethypamino)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamideas a crude residue. MS ESI calc'd. for C₂₃H₂₇ClF₃N₇O [M+H]⁺ 510, found510.

Step 3: To a reaction vessel containing the residue of4-(5-chloropyridin-3-yl)-N-hydroxy-2-(methyl(2,2,2-trifluoroethypamino)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamide(0.028 g, 0.056 mmol) suspended in acetonitrile (1.0 mL) was added DBU(0.025 mL, 0.17 mmol) and 1,1′-carbonyldiimidazole (0.020 g, 0.12 mmol).The reaction was allowed to stir at ambient temperature for 3 hours. Thereaction was concentated in vacuo and taken up in DMSO (1.0 mL) and waspassed through a syringe filter. The filtrate was purified by reversephase preparative HPLC (0:100 to 95:5 acetonitrile:water: 0.1% v/v TFAmodifier) to afford 3-(4-(5-chloropyridin-3-yl)-2-(methyl(2,2,2-trifluoroethyl)amino)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one,TFA salt. MS ESI calc'd. for C₂₄H₂₅ClF₃N₇O₂ [M+H]⁺ 536, found 536. ¹HNMR (500 MHz, DMSO-d₆) δ 12.89 (s, 1H), 8.98 (s, 1H), 8.80 (m, 1H), 8.52(s, 1H), 7.93 (s, 1H), 4.55 (m, 3H), 3.30 (s, 3H), 1.38 (m, 2H), 1.02(m, 2H), 0.67 (d, J=6.5, 3H), 0.48 (m, 7H).

Example 3.953-(4-(5-chloropyridin-3-yl)-2-((trans-4-methoxytetrahydrofuran-3-yl)(methyl)amino)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one

Step 1: Using a procedure analogous to that described in Example 3.94(Step 1), starting with2-bromo-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Preparative Example 3.1) and trans-4-aminotetrahydrofuran-3-ol(purchased from Chembridge Corporation),4-(5-chloropyridin-3-yl)-2-((trans-4-hydroxytetrahydrofuran-3-yl)amino)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrilewas prepared. MS ESI calc'd. for C₂₄H₂₇ClN₆O₂ [M+H]⁺ 467, found 467.

Step 2: To a reaction vessel containing the residue of4-(5-chloropyridin-3-yl)-2-((trans-4-hydroxytetrahydrofuran-3-yl)amino)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile(0.010 g, 0.021 mmol) suspended in THF (0.5 mL) was added NaH (0.0043 g,0.11 mmol, 60% dispersion in mineral oil). The reaction was allowed tostir at ambient temperature for 15 minutes. To the reaction vessel wasthen added iodomethane (0.025 mL, 0.40 mmol). The reaction vessel wassealed and warmed to 60° C. for 4 hours. The reaction was cooled toambient temperature and quenched with H₂O (2.0 mL) and was extractedwith EtOAc (2×5.0 mL). The collected organics were concentrated in vacuoto afford4-(5-chloropyridin-3-yl)-2-((trans-4-methoxytetrahydrofuran-3-yl)(methyl)amino)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrileas a crude residue. MS ESI calc'd. for C₂₆H₃₁ClN₆O₂ [M+H]⁺ 495, found495.

Step 3: Using a procedure analogous to that described in Example 3.94(Step 2) and starting with4-(5-chloropyridin-3-yl)-2-((trans-4-methoxytetrahydrofuran-3-yl)(methyl)amino)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile,4-(5-chloropyridin-3-yl)-N-hydroxy-2-((trans-4-methoxytetrahydrofuran-3-yl)(methyl)amino)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamidewas prepared. MS ESI calc'd. for C₂₆H₃₄ClN₇O₃ [M+H]⁺ 528, found 528.

Step 4: Using a procedure analogous to that described in Example 3.94(Step 3) and starting with4-(5-chloropyridin-3-yl)-N-hydroxy-2-((trans-4-methoxytetrahydrofuran-3-yl)(methyl)amino)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamide,3-(4-(5-chloropyridin-3-yl)-2-((trans-4-methoxytetrahydrofuran-3-yl)(methyl)amino)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one(TFA salt, racemic) was prepared. MS ESI calc'd. for C₂₇H₃₂ClN₇O₄ [M+H]⁺554, found 554. ¹H NMR (500 MHz, d6-dmso): δ 12.87 (s, 1H); 8.96 (s,1H); 8.80 (d, J=2.3 Hz, 1H); 8.50 (s, 1H); 7.93 (s, 1H); 4.35 (s, 1H);4.20 (s, 1H); 4.03 (dd, J=9.9, 6.1 Hz, 2H); 3.82-3.84 (m, 1H); 3.69-3.72(m, 3H); 3.63-3.65 (m, 2H); 3.07 (s, 3H); 1.36 (d, J=12.6 Hz, 2H);0.93-1.03 (m, 2H); 0.67 (d, J=6.5 Hz, 3H); 0.54-0.61 (m, 5H); 0.38-0.43(m, 2H).

Example 3.963-(4-(5-chloropyridin-3-yl)-2-(2-(1-methyl-1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one

Step 1: Using a procedure analogous to that described in Example 3.94(Step 1), starting with2-bromo-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Preparative Example 3.1) and 2-ethynylpyrrolidine,4-(5-chloropyridin-3-yl)-2-(2-ethynylpyrrolidin-1-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrilewas prepared. MS ESI calc'd. for C₂₆H₂₇ClN₆ [M+H]⁺ 459, found 459.

Step 2: Using a procedure analogous to that described in Example 3.94(Step 2), and starting with4-(5-chloropyridin-3-yl)-2-(2-ethynylpyrrolidin-1-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile,4-(5-chloropyridin-3-yl)-2-(2-ethynylpyrrolidin-1-yl)-N-hydroxy-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamidewas prepared. MS ESI calc'd. for C₂₆H₃₀ClN₇O [M+H]⁺ 492, found 492.

Step 3: Using a procedure analogous to that described in Example 3.94

(Step 3), and starting with4-(5-chloropyridin-3-yl)-2-(2-ethynylpyrrolidin-1-yl)-N-hydroxy-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamide,3-(4-(5-chloropyridin-3-yl)-2-(2-ethynylpyrrolidin-1-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-onewas prepared. MS ESI calc'd. for C₂₇H₂₈ClN₇O₂ [M+H]⁺ 518, found 518.

Step 4: To a reaction vessel were added DMSO (0.4 mL), sodium azide(0.005 g, 0.080 mmol) and iodomethane (0.006 mL, 0.085 mmol). Thereaction vessel was sealed and stirred at 50° C. for 12 hours. To thereaction was then added3-(4-(5-chloropyridin-3-yl)-2-(2-ethynylpyrrolidin-1-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one(0.020 g, 0.039 mmol), CuI (0.004 g, 0.019 mmol), and DIEA (0.015 mL,0.086 mmol). The reaction vessel was sealed and further stirred at 50°C. for 6 hours. To the reaction was added DMSO (0.6 mL), and thesolution was passed through a syringe filter. The filtrate was purifiedby reverse phase preparative HPLC (0:100 to 95:5 acetonitrile:water:0.1% v/v TFA modifier) to afford3-(4-(5-chloropyridin-3-yl)-2-(2-(1-methyl-1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one(TFA salt). MS ESI calc'd. for C₂₈H₃₁ClN₁₀O₂ [M+H]⁺ 575, found 575. ¹HNMR (500 MHz, DMSO-d₆): δ 12.81 (s, 1H); 8.85 (s, 1H); 8.77 (d, J=2.3Hz, 1H); 8.41 (s, 1H); 7.94 (s, 1H); 7.79 (s, 1H); 5.50 (t, J=7.1 Hz,1H); 3.94 (s, 3H); 3.80-3.86 (m, 3H); 3.43-3.46 (m, 1H); 2.37-2.39 (m,1H); 2.12-2.18 (m, 2H); 1.95-2.00 (m, 1H); 1.28-1.30 (m, 2H); 0.96-1.03(m, 2H); 0.66 (d, J=6.5 Hz, 4H); 0.41-0.44 (m, 3H); 0.30-0.36 (m, 2H).

Example 3.97(S)-1-(4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-N-ethyl-N-methylpyrrolidine-2-carboxamide

Step 1:(S)-1-(4-(5-chloropyridin-3-yl)-6-cyano-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-2-yl)pyrrolidine-2-carboxylicacid was prepared using a procedure analogous to that described inExample 3.94 (Step 1) using2-bromo-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Preparative Example 3.1) and L-proline. MS ESI calc'd. for C₂₅H₂₇ClN₆O₂[M+H]⁺ 479, found 479.

Step 2: To a reaction vessel was added the crude residue of(S)-1-(4-(5-chloropyridin-3-yl)-6-cyano-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-2-yl)pyrrolidine-2-carboxylicacid (0.030 g, 0.063 mmol), propylphosphonic anhydride (0.10 mL, 50% w/win DMF), and N-methylethanamine (0.0037 g, 0.063 mmol) suspended in DMF(0.5 mL). The reaction was stirred at ambient temperature for 6 hours.The reaction was diluted with H₂O (2.0 mL) and was extracted with EtOAc(2×5 mL). The combined organics were concentrated in vacuo to afford(S)-1-(4-(5-chloropyridin-3-yl)-6-cyano-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-2-yl)-N-ethyl-N-methylpyrrolidine-2-carboxamideas a crude residue. MS ESI calc'd. for C₂₈H₃₄ClN₇O [M+H]⁺ 520, found520.

Step 3: Using a procedure analogous to that described in Example 3.94(Step 2), and starting with(5)-1-(4-(5-chloropyridin-3-yl)-6-cyano-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-2-yl)-N-ethyl-N-methylpyrrolidine-2-carboxamide,(5)-1-(4-(5-chloropyridin-3-yl)-6-(N-hydroxycarbamimidoyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-2-yl)-N-ethyl-N-methylpyrrolidine-2-carboxamidewas prepared. MS ESI calc'd. for C₂₈H₃₇ClN₈O₂ [M+H]⁺ 553, found 553.

Step 4: Using a procedure analogous to that described in Example 3.94(Step 3), and starting with(S)-1-(4-(5-chloropyridin-3-yl)-6-(N-hydroxycarbamimidoyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-2-yl)-N-ethyl-N-methylpyrrolidine-2-carboxamide,(5)-1-(4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-N-ethyl-N-methylpyrrolidine-2-carboxamide(TFA salt) was prepared. MS ESI calc'd. for C₂₉H₃₅ClN₈O₃ [M+H]⁺ 579,found 579. ¹H NMR (500 MHz, DMSO-d₆) δ 12.79 (s, 1H), 8.89 (m, J=7.9,1H), 8.77 (d, J=2.3, 1H), 8.46 (m, 1H), 7.69 (d, J=17.4, 1H), 5.14 (m,1H), 3.88 (m, 1H), 3.72 (m, 1H), 3.53 (m, 2H), 3.27 (m, 1H), 3.15 (s,2H), 2.79 (s, 2H), 2.35 (m, 1H), 2.06 (m, 1H), 1.93 (m, 1H), 1.78 (m,1H), 1.30 (m, J=7.1, 5H), 1.07 (m, J=7.1, 3H), 0.69 (d, J=6.5, 3H), 0.55(m, 5H).

Example 3.983-(4-(5-chloropyridin-3-yl)-2-(2-fluorophenyl)amino)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one

Step 1: To a sealed tube were added2-bromo-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Preparative Example 3.1) (0.010 g, 0.045 mmol), 2-fluoroaniline (0.0050g, 0.045 mmol), Cs₂CO₃ (0.022 g, 0.067 mmol),chloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II)(0.0050 g, 0.0056 mmol), and dioxane (0.5 mL). The reaction vessel waspurged with argon, sealed and warmed to 75° C. for 8 hours withstirring. The reaction was cooled and diluted with dioxane (1.0 mL) andwas passed through a syringe filter. The collected eluent wasconcentrated in vacuo to afford4-(5-chloropyridin-3-yl)-2-((2-fluorophenyl)amino)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrileas a crude residue. MS ESI calc'd. for C₂₆H₂₄ClFN₆ [M+H]⁺ 475, found475.

Step 2: Using a procedure analogous to that described in Example 3.94(Step 2), and starting with4-(5-chloropyridin-3-yl)-2-(2-fluorophenyl)amino)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile,4-(5-chloropyridin-3-yl)-2-(2-fluorophenyl)amino)-N-hydroxy-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamidewas prepared. MS ESI calc'd. for C₂₆H₂₇ClFNγO [M+H]⁺ 508, found 508.

Step 3: Using a procedure analogous to that described in Example 3.94(Step 3), and starting with4-(5-chloropyridin-3-yl)-2-(2-fluorophenyl)amino)-N-hydroxy-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamide,3-(4-(5-chloropyridin-3-yl)-2-(2-fluorophenyl)amino)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one(TFA salt) was prepared. MS ESI calc'd. for C₂₇H₂₅ClFNγO₂ [M+H]⁺ 534,found 534. ¹H NMR (500 MHz, DMSO-d₆) δ 12.83 (s, 1H), 9.27 (s, 1H), 8.83(m, J=20.7, 2H), 8.39 (s, 1H), 7.81 (s, 1H), 7.65 (m, 1H), 7.26 (m, 3H),3.85 (s, 2H), 1.44 (d, 2H), 1.07 (m, 2H), 0.71 (m, J=6.5, 7H), 0.54 (m,2H)

Example 3.120(4aS,7aS)-4-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-1-methyloctahydro-2H-cyclopenta[b]pyrazin-2-one

Step 1: tert-Butyl [(1S,2S)-2-aminocyclopentyl]carbamate (900 mg, 4.49mmol) (purchased from Sigma Aldrich) was taken up in acetonitrile (13mL). Potassium carbonate (932 mg, 6.74 mmol) and ethyl chloroacetate(0.577 mL, 5.39 mmol) were added, and the resulting mixture was heatedto 55° C. overnight. The resulting mixture was cooled to roomtemperature and concentrated under reduced pressure. The residue wastaken up in EtOAc, washed with water and brine, dried over magnesiumsulfate, filtered, and concentrated under reduced pressure. Theresulting residue was purified by silica gel chromatography (0-100%EtOAc/hexanes) to afford ethylN-{(1S,2S)-2-[(tert-butoxycarbonyl)amino]cyclopentyl}glycinate.

Step 2: EthylN-{(1S,2S)-2-[(tert-butoxycarbonyl)amino]cyclopentyl}glycinate (910 mg,3.18 mmol) was taken up in dioxane (16 mL) and HCl (7.5 mL of 4 M indioxane, 30.0 mmol) was added. The resulting mixture was stirred at roomtemperature overnight. The mixture was concentrated under reducedpressure to afford ethyl N-[(1S,2S)-2-aminocyclopentyl]glycinate (HClsalt) which was used without further purification.

Step 3: Ethyl N-[(1S,2S)-2-aminocyclopentyl]glycinate (HCl salt) (708mg, 3.18 mmol) was dissolved in ethanol (16 mL), and triethylamine (4.43mL, 31.8 mmol) was added. The resulting mixture was stirred and heatedat 85° C. for 24 hours. The mixture was then cooled and concentratedunder reduced pressure. Ethyl acetate was added to the residue, and theresulting slurry was filtered. The filtrate was concentrated underreduced pressure to afford(4aS,7aS)-octahydro-2H-cyclopenta[b]pyrazin-2-one, which was usedwithout further purification. ¹H NMR (500 MHz, CDCl₃) δ 6.31 (s, 1H),3.68-3.67 (m, 2H), 3.23-3.17 (m, 1H), 2.86-2.81 (m, 1H), 1.97-1.82 (m,5H), 1.49-1.40 (m, 2H).

Step 4: A vial was charged with potassium fluoride (163 mg, 2.81 mmol),2-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Preparative Example 3.1, 250 mg, 0.562 mmol),(4aS,7aS)-octahydro-2H-cyclopenta[b]pyrazin-2-one (189 mg, 1.349 mmol),DMSO (1730 μl) and DIEA (491 μl, 2.81 mmol). The vial was capped andheated to 100° C. overnight. The mixture was then cooled to roomtemperature, diluted with ethyl acetate and washed with water and brine.The organic layer was dried over magnesium sulfate, filtered, andconcentrated. Purification by silica gel chromatography (0-20% MeOH inDCM) afforded4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(4aS,7aS)-3-oxooctahydro-1H-cyclopenta[b]pyrazin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ESI calc'd. for C₂₇H₃₀ClN₇O [M+H]⁺ 504, found 504.

Step 5:4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(4aS,7aS)-3-oxooctahydro-1H-cyclopenta[b]pyrazin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(282 mg, 0.559 mmol) was taken up in DMF (5595 μl), and sodium hydride(22.38 mg, 0.559 mmol) and iodomethane (87 μl, 1.399 mmol) were added.The mixture was stirred for 1 hour, quenched via the addition ofsaturated aqueous ammonium chloride and extracted with ethyl acetate.The organic layer was dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. The resulting residue was purifiedvia silica gel chromatography (0-20% MeOH/DCM) to afford4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(4aS,7aS)-4-methyl-3-oxooctahydro-1H-cyclopenta[b]pyrazin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrileas a brown foam. MS ESI calc'd. for C₂₈H₃₂ClN₇O [M+H]⁺ 518, found 518.

Step 6:4-(5-Chloropyridin-3-yl)-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-2-[(4aS,7aS)-4-methyl-3-oxooctahydro-1H-cyclopenta[b]pyrazin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carboximidamidewas prepared in analogy to Example 3.1, Step 2 using4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(4aS,7aS)-4-methyl-3-oxooctahydro-1H-cyclopenta[b]pyrazin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(185 mg, 0.357 mmol) as starting material. MS ESI calc'd. forC₂₈H₃₅ClN₈O₂ [M+H]⁺ 551, found 551.

Step 7:(4aS,7aS)-4-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-1-methyloctahydro-2H-cyclopenta[b]pyrazin-2-onewas prepared in analogy to Example 3.1, Step 3 using4-(5-chloropyridin-3-yl)-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-2-[(4aS,7aS)-4-methyl-3-oxooctahydro-1H-cyclopenta[b]pyrazin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide(197 mg, 0.357 mmol) as starting material and 0-20% methanol in DCM aseluant for chromatography. MS ESI calc'd. for C₂₉H₃₃ClN₈O₃ [M+H]⁺ 577,found 577. ¹H NMR (500 MHz, DMSO-d₆) δ 12.89 (s, 1H), 8.98 (d, J=2.0 Hz,1H), 8.81 (d, J=2.0 Hz, 1H), 8.49 (t, J=2.0 Hz, 1H), 8.04 (s, 1H),4.31-4.28 (m, 1H), 3.88-3.84 (m, 2H), 3.69-3.61 (m, 3H), 2.88 (s, 3H),2.34-2.24 (m, 1H), 2.31-2.04 (m, 1H), 1.89-1.75 (m, 2H), 1.70-1.61 (m,1H), 1.47-1.33 (m, 3H), 1.25-1.20 (m, 2H), 1.08-0.98 (m, 1H), 0.85-0.82(m, 1H), 0.73-0.60 (m, 5H), 0.62-0.33 (m, 2H).

Examples 3.127 and 3.1283-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(4aR,8aR)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-oneand3-{2-[(4aR,8aR)-6-benzyloctahydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl]-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one

To benzyl(4aR,8aR)-1-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl]octahydro-6H-pyrido[3,4-b][1,4]oxazine-6-carboxylate(Example 3.126, prepared in analogy to Example 3.1, starting withPreparative Example 3.1 and Preparative Example 3.2, 58.7 mg, 0.08 mmol)dissolved in DCM (3.2 mL) at 0° C. under an argon atmosphere was addediodotrimethylsilane (60 μL, 0.42 mmol). The reaction was stirred for 1hour at room temperature. Isopropanol (1.5 mL) and aqueous sodiumcarbonate solution (2 M, 3 mL) were added, and the biphasic reaction wasstirred for 1 hour. The organic layer was separated, and the aqueouslayer was extracted with DCM (3×). The combined organic layers weredried over sodium sulfate, filtered, and concentrated. The residue waspurified by mass triggered, reverse phase (C-18) preparative HPLC(acetonitrile:water: 0.1% v/v trifluoroacetic acid modifier) to afford3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(4aR,8aR)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-oneas a TFA salt. MS ESI calc'd. for C₂₈H₃₃ClN₈O₃ [M+H]⁺ 565, found 565. ¹HNMR (500 MHz, DMSO-d₆) δ 12.94 (s, 1H), 8.95 (s, 1H), 8.83 (d, J=2.0,1H), 8.63 (s, 1H), 8.47 (s, 1H), 8.13 (s, 1H), 4.01-3.86 (m, 3H),3.72-3.57 (m, 3H), 3.54-3.48 (m, 2H), 3.10-2.92 (m, 3H), 2.74 (s, 1H),1.46-1.39 (m, 1H), 1.37-1.29 (m, 2H), 1.06 (s, 1H), 0.81 (s, 1H),0.76-0.67 (m, 6H), 0.53 (s, 1H), 0.48-0.31 (m, 3H). Also isolated was3-{2-[(4aR,8aR)-6-benzyloctahydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl]-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-oneMS ESI calc'd. for C₃₅H₃₉ClN₈O₃ [M+H]⁺ 655, found 655.

Example 3.1413-(4-(5-chloropyridin-3-yl)-2-(2S,4R)-2-(difluoromethyl)-4-methoxypyrrolidin-1-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one

Step 1: To a vial were added ((2S,4R)-4-methoxypyrrolidin-2-yl)methanol,HCl (0.303 g, 1.81 mmol),2-bromo-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Preparative Example 3.1) (0.805 g, 1.810 mmol), potassium fluoride(0.210 g, 3.62 mmol), DMSO (4 ml) and DIEA (0.948 ml, 5.43 mmol). Thereaction vial was capped and heated to 100° C. for 8 h. The reactionmixture was cooled to room temperature, diluted with ethyl acetate, andwashed with water and then brine. The organic layer was dried oversodium sulfate, filtered, and concentrated under reduced pressure.

The residue was purified by silica gel chromatography (0-100% ethylacetate/hexanes, linear gradient) to afford4-(5-chloropyridin-3-yl)-2-(2S,4R)-2-(hydroxymethyl)-4-methoxypyrrolidin-1-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ESI calc'd. for C₂₆H₃₁ClN₆O₂ [M+H]⁺ 495, found 495.

Step 2: A solution of oxalyl chloride (0.160 ml, 1.826 mmol) indichloromethane (5 ml) was cooled to −78° C., and a solution of DMSO(0.259 ml, 3.65 mmol) in dichloromethane (2.5 ml) was slowly added. Thereaction was warmed to −60° C. After 10 min of stirring, a solution of4-(5-chloropyridin-3-yl)-2-((2S,4R)-2-(hydroxymethyl)-4-methoxypyrrolidin-1-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile(452 mg, 0.913 mmol) in dichloromethane (5 ml) was slowly added. Thereaction was stirred for 30 min at −40° C. Then triethylamine (0.764 ml,5.48 mmol) was added, and the reaction was warmed to room temperatureand stirred overnight. The reaction mixture was quenched with saturatedaqueous NaHCO₃ (30 mL). The dichloromethane layer was separated. Theaqueous layer was extracted with dichloromethane (20 mL). The combineddichloromethane layers were washed with brine (50 mL), dried overNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel, eluting with EtOAc/isohexane togive4-(5-chloropyridin-3-yl)-2-(2S,4R)-2-formyl-4-methoxypyrrolidin-1-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ESI calc'd. for C₂₆H₂₉ClN₆O₂ [M+H]⁺ 493, found 493.

Step 3: To a solution of4-(5-chloropyridin-3-yl)-2-(2S,4R)-2-formyl-4-methoxypyrrolidin-1-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile(360 mg, 0.730 mmol) in dichloromethane (10 ml) was added dropwisedeoxofluor (0.296 ml, 1.606 mmol) at −60° C. The resulting mixture wasstirred at room temperature overnight. The reaction mixture was quenchedwith 5% aqueous Na₂CO₃ (30 mL) at 0° C. The dichloromethane layer wasseparated. The aqueous layer was extracted with dichloromethane (20 mL).The combined dichloromethane layers were washed with brine (50 mL),dried over Na₂SO₄, filtered, and concentrated in vacuo. The cruderesidue containing4-(5-chloropyridin-3-yl)-2-(2S,4R)-2-(difluoromethyl)-4-methoxypyrrolidin-1-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrilewas used in the next step. MS ESI calc'd. for C₂₆H₂₉ClF₂N₆O [M+H]⁺ 515,found 515.

Steps 4 & 5: Using a procedure analogous to that described in Example3.1 (Step 2 and Step 3), and starting with4-(5-chloropyridin-3-yl)-2-(2S,4R)-2-(difluoromethyl)-4-methoxypyrrolidin-1-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile,3-(4-(5-chloropyridin-3-yl)-2-(2S,4R)-2-(difluoromethyl)-4-methoxypyrrolidin-1-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one,TFA salt was prepared. MS ESI calc'd. for C₂₇H₃₀ClF₂N₇O₃ [M+H]⁺ 574,found 574. ¹H NMR (500 MHz, DMSO-d6) δ 8.97 (s, 1H); 8.79 (s, 1H); 8.50(s, 1H); 7.90 (s, 1H); 6.17 (t, J=56.1 Hz, 1H); 4.85 (br s, 1H); 4.08(s, 1H); 3.79-3.85 (m, 3H); 3.52-3.60 (m, 1H); 3.21 (s, 3H); 2.31 (dd,J=13.8, 7.6 Hz, 1H); 2.00-2.06 (m, 1H); 1.36 (br s, 3H); 1.02 (br s,3H); 0.86 (d, J=12.5 Hz, 1H); 0.67 (d, J=6.5 Hz, 3H); 0.39-0.67 (m, 4H).

Example 3.1723-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(pyridin-2-ylamino)-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one

Step 1: To a solution of2-bromo-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Preparative Example 3.1) (0.5 g, 1.128 mmol) in toluene (5 mL) in apyrex tube, 2-aminopyridine (0.127 g, 1.35 mmol), and BINAP (35 mg,0.056 mmol) were added, and the reaction mixture was degassed with argonfor 5 minutes. Pd₂(dba)₃ (51 mg, 0.056 mmol) and potassium tert-butoxide(0.189 g, 1.69 mmol) were added, and the tube was capped and heated to100° C. for 17 h. The reaction mixture was cooled to room temperature,and the solvent was removed under reduced pressure, The residue wasdissolved in ethyl acetate (20 mL), washed with water (5 mL) and brine(5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified on a silica gel column using40% ethyl acetate/petroleum ether as eluent to give4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(pyridin-2-ylamino)-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ES/APCl calc'd. for C₂₅H₂₄ClN₇ [M+H]⁺ 458, found 458.

Steps 2 & 3: Using procedures analagous to those described in Example3.1 (Steps 2 and 3),4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(pyridin-2-ylamino)-3H-imidazo[4,5-c]pyridine-6-carbonitrilewas converted to3-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(pyridin-2-ylamino)-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one(TFA salt). ¹H NMR (400 MHz, CD₃OD): δ 8.81 (s, 1H), 8.33 (s, 1H), 8.26(d, J=4.4 Hz, 1H), 8.20 (t, J=8.8 Hz, 1H), 8.11 (s, 1H), 7.66 (d, J=8.8Hz, 1H), 7.28-7.11 (m, 2H), 3.92 (d, J=6.4 Hz, 2H), 1.55 (d, J=12.4 Hz,2H), 1.26-1.04 (m, 4H), 0.97-0.84 (m, 2H), 0.79 (d, J=6.4 Hz, 3H),0.71-0.55 (m, 2H). MS ES/APCl calc'd. for C₂₆H₂₅ClN₈O₂ [M+H]⁺ 517, found517.

Example 3.1734-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(pyridin-2-ylamino)-3H-imidazo[4,5-c]pyridine-6-carboxylicacid

4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(pyridin-2-ylamino)-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Example 3.172, Step 1) (60 mg, 0.131 mmol) was placed in a pyrex tube,and conc. HCl (2 mL) was added. The tube was capped and heated to 80° C.for 2 h. The reaction mixture was concentrated and the residue obtainedwas purified by reverse phase prep-HPLC (Kromasil C18,water/acetonitrile+0.1% TFA) to give4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(pyridin-2-ylamino)-3H-imidazo[4,5-c]pyridine-6-carboxylicacid (TFA salt). ¹H NMR (400 MHz, CDCl₃): δ 8.83 (s, 1H), 8.82 (s, 1H),8.74 (s, 1H), 8.51 (s, 1H), 8.26-8.22 (m, 2H), 7.99 (s, 1H), 7.33-7.32(m, 1H), 4.07 (d, J=6.4 Hz, 2H), 1.52 (d, J=12.1 Hz, 2H), 1.20-1.09 (m,2H), 0.94-0.80 (m, 4H), 0.77 (d, J=6.5 Hz, 3H), 0.62-0.56 (m, 2H). MSES/APCl calc'd. for C₂₅H₂₅ClN₆O₂ [M+H]⁺ 477, found 477.

Example 3.1743-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[methyl(phenyl)amino]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one

Step 1: To a solution of2-bromo-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Preparative Example 3.1, 500 mg, 1.35 mmol) in toluene (5 mL), wasadded aniline (0.13 mL, 1.48 mmol) andchloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II)(BrettPhos precatalyst, 107 mg, 0.135 mmol), and the reaction wasdeoxygenated by purging with nitrogen for 10 minutes. Sodiumtert-butoxide (194 mg, 2.02 mmol) in THF (2 mL) was added, and thereaction was again purged with nitrogen for 5 minutes. The reactionflask was sealed, and the mixture was stirred at room temperature for 2hours. The reaction mixture was diluted with EtOAc (100 mL) and thelayers were separated. The organic layer was washed with water (2×25 mL)followed by saturated brine solution (25 mL). The organic layer wasdried over anhydrous Na₂SO₄ and concentrated. The crude product waspurified on a silica gel column (30% EtOAc/petroleum ether) to afford4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(phenylamino)-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ES/APCl calc'd. for C₂₆H₂₅ClN₆ [M+H]⁺ 457, found 457.

Step 2: DMF (4 mL) was added to a vial containing4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(phenylamino)-3H-imidazo[4,5-c]pyridine-6-carbonitrile(200 mg, 0.438 mmol), followed by methyl iodide (68 mg, 0.481 mmol) andpotassium carbonate (121 mg, 0.877 mmol), and the vial was sealed andheated to 60° C. for 2 hours. The reaction mixture was cooled to roomtemperature, diluted with ethyl acetate, and washed with water andbrine. The organic layer was dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography using 15% ethylacetate/petroleum ether as eluent to afford4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[methyl(phenyl)amino]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ES/APCl calc'd. for C₂₇H₂₇ClN₆ [M+H]⁺ 471, found 471.

Step 3 & 4: Using procedures similar to those described in Example 3.1(Steps 2 and 3),4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[methyl(phenyl)amino]-3H-imidazo[4,5-c]pyridine-6-carbonitrilewas converted to3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[methyl(phenyl)amino]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(TFA salt). MS ES/APCl calc'd. for C₂₈H₂₈ClN₇O₂ [M+H]⁺ 530, found 530.¹H NMR (400 MHz, DMSO-d₆): δ 12.95 (s, 1H), 8.82 (d, J=3.5 Hz, 2H), 8.40(bs, 1H), 7.96 (s, 1H), 7.35 (t, J=7.1 Hz, 2H), 7.10-7.00 (m, 3H), 3.45(s, 2H), 3.35 (bs, 3H), 1.42-1.40 (m, 2H), 1.02-0.97 (m, 2H), 0.85-0.83(m, 2H), 0.70 (d, J=6.4 Hz, 3H), 0.59-0.53 (m, 4H).

Example 3.1754-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[methyl(phenyl)amino]-3H-imidazo[4,5-c]pyridine-6-carboxylicacid

To a solution of4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[methyl(phenyl)amino]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Example 3.174 step 2, 160 mg, 0.339 mmol) in methanol (2 mL) in asealable tube was added 30% sodium hydroxide solution (4 mL). The tubewas sealed and heated to 80° C. for 14 hours. The reaction mixture wascooled to room temperature and neutralized with the addition of 1.5 MHCl solution. The solution was extracted with ethyl acetate (4×25 mL).The organic layer was dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified bypreparative HPLC (Kromasil C18, water/acetonitrile+0.1% TFA modifier) toafford4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[methyl(phenyl)amino]-3H-imidazo[4,5-c]pyridine-6-carboxylicacid (TFA salt). MS ES/APCl calc'd. for C₂₇H₂₈ClN₆O₂ [M+H]⁺ 490, found490. ¹H NMR (400 MHz, DMSO-d₆): δ 12.79 (bs, 1H), 8.78 (d, J=12.8 Hz,2H), 8.30 (s, 1H), 7.82 (s, 1H), 7.26 (t, J=7.6 Hz, 2H), 6.96-6.87 (m,3H), 3.40-3.30 (m, 2H), 3.21 (s, 3H), 1.46-1.42 (m, 2H), 1.26-1.01 (m,4H), 0.86-0.84 (m, 3H), 0.73-0.71 (m, 4H).

The compounds in Table 3 were prepared as described above or usingprocedures which were analogous to those described above. In some cases,enantiomers or diastereomers were separated by chromatography on chiralcolumns using standard techniques. Amines used to displace the bromideof Preparative Example 3.1 are described above, commercially available,known in the literature, or can be prepared using methods readilyavailable in the literature.

TABLE 3 FRET IC₅₀ [M + H]⁺ [M + H]⁺ Ex. (nM) Structure Chemical NameSalt Calc'd Obsv'd 3.1 1

3-{4-(5- chloropyridin-3- yl)-2-[(2S)-2- (fluoromethyl)pyrrolidin-1-yl]-3- [(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one 526 526 3.2 1

3-{4-(5- chloropyridin-3- yl)-2- ((4aR,7aR)- hexahydrocyclo-penta[b][1,4] oxazin-4(4aH)-yl)- 3-[(trans-4- methylcyclohexyl)methyl]-3H- imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one 550550 3.3 1

3-(4-(5- chloropyridin-3- yl)-3-((trans-4- methylcyclohexyl)methyl)-2-((S)-2- (trifluoromethyl) pyrrolidin-1-yl)- 3H-imidazo[4,5-c]pyridin-6-yl)- 1,2,4-oxadiazol- 5(4H)-one 562 562 3.4 2

3-{4-(5- chloropyridin-3- yl)-2- (hexahydrocyclo- penta[b][1,4]oxazin-4(4aH)- yl)-3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (racemic) 550550 3.5 4

3-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl) methyl]-2-(octahydro-4H- 1,4-benzoxazin- 4-yl)-3H- imidazo[4,5- c]pyridin-6-yl]-1,2,4-oxadiazol- 5(4H)-one (racemic) 564 564 3.6 4

5-{4-(5- chloropyridin-3- yl)-2- (hexahydrocyclo- penta[b][1,4]oxazin-4(4aH)- yl)-3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,3,4-oxadiazol- 2(3H)-one (racemic) TFA550 550 3.7 1

3-{4-(5- chloropyridin-3- yl)-2-[(2S)-2-(1- methoxy-1- methylethyl)pyrrolidin-1-yl]- 3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 566 566 3.84

5-{4-(5- chloropyridin-3- yl)-2-[(2S)-2- (fluoromethyl)pyrrolidin-1-yl]-3- [(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,3,4-oxadiazol- 2(3H)-one TFA 526 526 3.959

3-{4-(5- chloropyridin-3- yl)-2- ((4aS,7aS)- hexahydrocyclopenta[b][1,4] oxazin-4(4aH)-yl)- 3-[(trans-4- methylcyclohexyl)methyl]-3H- imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one 550550 3.10 1

3-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl) methyl]-2-(octahydro-4H- 1,4-benzoxazin- 4-yl)-3H- imidazo[4,5- c]pyridin-6-yl]-1,2,4-oxadiazol- 5(4H)-one (enantiomer 1) 564 564 3.11 17

3-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl) methyl]-2-(octahydro-4H- 1,4-benzoxazin- 4-yl)-3H- imidazo[4,5- c]pyridin-6-yl]-1,2,4-oxadiazol- 5(4H)-one (enantiomer 2) 564 564 3.12 7

5-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl) methyl]-2-(octahydro-4H- 1,4-benzoxazin- 4-yl)-3H- imidazo[4,5- c]pyridin-6-yl]-1,3,4-oxadiazol- 2(3H)-one (racemic) TFA 564 564 3.13 2

5-{4-(5- chloropyridin-3- yl)-2-[(2S)-2-(1- methoxy-1- methylethyl)pyrrolidin-1-yl]-3- [(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,3,4-oxadiazol- 2(3H)-one TFA 566 5663.14 164

5-{4-(5- chloropyridin-3- yl)-2- ((4aS,7aS)- hexahydrocyclo-penta[b][1,4] oxazin-4(4aH)-yl)- 3-[(trans-4- methylcyclohexyl)methyl]-3H- imidazo[4,5- c]pyridin-6-yl}- 1,3,4-oxadiazol- 2(3H)-one 550550 3.15 2

5-{4-(5- chloropyridin-3- yl)-2- ((4aR,7aR)- hexahydrocyclo-penta[b][1,4] oxazin-4(4aH)-yl)- 3-[(trans-4- methylcyclohexyl)methyl]-3H- imidazo[4,5- c]pyridin-6-yl}- 1,3,4-oxadiazol- 2(3H)-one 550550 3.16 2

3-{4-(5- chloropyridin-3- yl)-2-[(3R,5R)- 3,5- dimethylmorpholin-4-yl]-3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one 538 538 3.18 62

5-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl) methyl]-2-(octahydro-4H- 1,4-benzoxazin- 4-yl)-3H- imidazo[4,5- c]pyridin-6-yl]-1,3,4-oxadiazol- 2(3H)-one (enantiomer 1) 564 564 3.19 4

5-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl) methyl]-2-(octahydro-4H- 1,4-benzoxazin- 4-yl)-3H- imidazo[4,5- c]pyridin-6-yl]-1,3,4-oxadiazol- 2(3H)-one (enantiomer 2) 564 564 3.20 7

5-{4-(5- chloropyridin-3- yl)-2-[(3R,5R)- 3,5- dimethylmorpholin-4-yl]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,3,4-oxadiazol- 2(3H)-one TFA 538 538 3.21 2

5-{4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-[(2S)-2- (trifluoromethyl) pyrrolidin-1-yl]- 3H-imidazo[4,5-c]pyridin-6-yl}- 1,3,4-oxadiazol- 2(3H)-one TFA 562 562 3.22 1

4-(5- chloropyridin-2- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-[(3R)-3- phenylmorpholin- 4-yl]-3H- imidazo[4,5-c] pyridine-6-carboxylic acid TFA 546 546 3.23 4

3-{4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-[(3R)-3- methylmorpholin- 4-yl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 524 524 3.24 157

3-{4-(5- chloropyridin-3- yl)-2-[(3S,5S)-3,5- dimethylmorpholin-4-yl]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 538 538 3.26 2

3-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl) methyl]-2-(octahydro-1H- cyclopenta[b] pyridin-1-yl)-3H- imidazo[4,5-c]pyridin-6-yl]- 1,2,4-oxadiazol- 5(4H)-one (mixture of stereoisomers)548 548 3.27 2

3-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl) methyl]-2-(octahydro-1H- cyclopenta[b] pyridin-1-yl)-3H- imidazo[4,5-c]pyridin-6-yl]- 1,2,4-oxadiazol- 5(4H)-one (stereoisomer 1) 548 548 3.2863

3-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl) methyl]-2-(octahydro-1H- cyclopenta[b] pyridin-1-yl)-3H- imidazo[4,5-c]pyridin-6-yl]- 1,2,4-oxadiazol- 5(4H)-one (stereoisomer 2) 548 5483.29 58

3-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl) methyl]-2-(octahydro-1H- cyclopenta[b] pyridin-1-yl)-3H- imidazo[4,5-c]pyridin-6-yl]- 1,2,4-oxadiazol- 5(4H)-one (stereoisomer 3) 548 5483.30 1

3-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl) methyl]-2-(octahydro-1H- cyclopenta[b] pyridin-1-yl)-3H- imidazo[4,5-c]pyridin-6-yl]- 1,2,4-oxadiazol- 5(4H)-one (stereoisomer 4) 548 5483.31 32

3-{4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-[6- (trifluoromethyl)-2- azabicyclo[3.1.0] hex-2-yl]-3H-imidazo[4,5-c] pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 574 5743.32 3

3-{4-(5- chloropyridin-3- yl)-2-(3- ethylmorpholin- 4-yl)-3-[(trans-4-methylcyclohexyl) methyl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one TFA 538 538 3.33 43

3-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-(2- oxa-5- azabicyclo[4.1.0] hept-5-yl)-3H- imidazo[4,5-c]pyridin-6-yl]- 1,2,4-oxadiazol- 5(4H)-one TFA 522 522 3.34 156

3-{4-(5- chloropyridin-3- yl)-2-(2,5- dimethylmorpholin- 4-yl)-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one (diastereoisomer 1) TFA 538 538 3.35 16

3-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-(3- methyl-1,4- oxazepan-4-yl)- 3H-imidazo[4,5-c]pyridin-6-yl]- 1,2,4-oxadiazol- 5(4H)-one TFA 538 538 3.36 1

3-{4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-[2- (1-methylethyl) pyrrolidin-1-yl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 536 536 3.37 2

3-{4-(5- chloropyridin-3- yl)-2-[(2R,5R)-2,5- dimethylpyrrolidin-1-yl]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 522 522 3.38 20

3-{4-(5- chloropyridin-3- yl)-2-(2,5- dimethylmorpholin-4-yl)-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (diastereoisomer 2) TFA 538538 3.39 1

4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl) methyl]-2-[(2S)-2- (trifluoromethyl) pyrrolidin-1-yl]- 3H-imidazo[4,5-c]pyridine-6- carboxylic acid TFA 522 522 3.40 1

3-{4-(5- chloropyridin-3- yl)-2-[3-(2- fluorophenyl) morpholin-4-yl]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one (racemic) 604 604 3.41 961

3-{4-(5- chloropyridin-3- yl)-2-[2-(1- methoxyethyl) pyrrolidin-1-yl]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one (stereoisomer 1) TFA 552 552 3.42 3

3-{4-(5- chloropyridin-3- yl)-2-[2-(1- methoxyethyl) pyrrolidin-1-yl]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one (stereoisomer 2) TFA 552 552 3.43 <1

3-{4-(5- chloropyridin-3- yl)-2-[3-(2- fluorophenyl) morpholin-4-yl]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one (enantiomer 1) 604 604 3.44 8

3-{4-(5- chloropyridin-3- yl)-2-[3-(2- fluorophenyl) morpholin-4-yl]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one (enantiomer 2) 604 604 3.45 9

3-{4-(5- chloropyridin-3- yl)-2-(2,3- dimethylpyrrolidin-1-yl)-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 522 522 3.46 1

3-{4-(5- chloropyridin-3- yl)-2-(2-cyclo- propylpyrrolidin-1-yl)-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 534 534 3.47 3

3-{2-(2-tert- butylpyrrolidin- 1-yl)-4-(5- chloropyridin-3-yl)-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 550 550 3.48 8

3-{2-(5- azaspiro[3.4]oct-5- yl)-4-(5- chloropyridin-3- yl)-3-[(trans-4-methylcyclohexyl) methyl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one TFA 534 534 3.49 2

3-{4-(5- chloropyridin-3- yl)-2-[2-(1,1- dimethylpropyl)pyrrolidin-1-yl]- 3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 564 5643.50 1

3-{4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-[2- (4-methyl-1,2,5- oxadiazol-3- yl)pyrrolidin-1- yl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 576 5763.51 4

3-{4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl) methyl]-2-[(2R)-2- methylpiperidin- 1-yl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one TFA 522 522 3.52 6

3-{4-(5- chloropyridin-3- yl)-2-[(2R,4R)- 4-hydroxy-2- methylpyrrolidin-1-yl]-3-[(trans- 4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 524 524 3.53 1

3-{4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-[2- (4-methyl-1,2,5- oxadiazol-3- yl)pyrrolidin-1- yl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (enantiomer 1)TFA 576 576 3.54 80

3-{4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-[2- (4-methyl-1,2,5- oxadiazol-3- yl)pyrrolidin-1- yl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (enantiomer 2)TFA 576 576 3.55 2

4-(5- chloropyridin-3- yl)-2- ((4aR,7aR)- hexahydrocyclo penta[b][1,4]oxazin-4(4aH)-yl)- 3-((trans-4- methylcyclohexyl) methyl)-3H-imidazo[4,5- c]pyridine-6- carboxylic acid TFA 510 510 3.56 3

4-(5- chloropyridin-3- yl)-2-[(2S)-2- (fluoromethyl) pyrrolidin-1-yl]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5- c]pyridine-6-carboxylic acid TFA 486 486 3.57 2

3-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl) methyl]-2-(trans-2-methyl-5- phenylmorpholin- 4-yl)-3H- imidazo[4,5-c]pyridin-6-yl]- 1,2,4-oxadiazol- 5(4H)-one (racemic) TFA 600 600 3.58 4

3-{4-(5- chloropyridin-3- yl)-2-[(2R,4R)- 4-methoxy-2-methylpyrrolidin-1- yl]-3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 538 5383.59 1

3-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl) methyl]-2-(trans-2-methyl-5- phenylmorpholin-4- yl)-3H-imidazo[4,5-c]pyridin-6-yl]- 1,2,4-oxadiazol- 5(4H)-one (enantiomer 1) TFA 600 6003.60 16

3-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl) methyl]-2-(trans-2-methyl-5- phenylmorpholin-4- yl)-3H- imidazo[4,5-c]pyridin-6-yl]- 1,2,4-oxadiazol- 5(4H)-one (enantiomer 2) TFA 600 6003.61 29

3-{4-(5- chloropyridin-3- yl)-2- (hexahydro-4H- furo[3,4-b][1,4]oxazin-4- yl)-3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 552 5523.62 54

1-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-6-(5- oxo-4,5- dihydro-1,2,4- oxadiazol-3-yl)- 3H-imidazo[4,5-c]pyridin-2-yl]- N,N-dimethyl-D- prolinamide TFA 565 565 3.63 35

1-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-6-(5- oxo-4,5- dihydro-1,2,4- oxadiazol-3-yl)- 3H-imidazo[4,5-c]pyridin-2-yl]- N-ethyl-N- methy-D- prolinoamide TFA 579 579 3.64 17

3-{4-(5- chloropyridin-3- yl)-2-[2-(3-ethyl- 5- methylisoxazol-4-yl)pyrrolidin-1- yl]-3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 603 6033.65 2

3-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-{2-[(1- methylethoxy) methyl]pyrrolidin- 1-yl}-3H-imidazo[4,5- c]pyridin-6-yl]- 1,2,4-oxadiazol- 5(4H)-one (enantiomer 1)TFA 566 566 3.66 7

3-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-{2- [(trifluoromethoxy) methyl]pyrrolidin- 1-yl}-3H-imidazo[4,5- c]pyridin-6-yl]- 1,2,4-oxadiazol- 5(4H)-one TFA 592 5923.67 4

3-{4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-[(2R)-2- methylpyrrolidin- 1-yl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 508 508 3.68 3

3-{4-(5- chloropyridin-3- yl)-2-[(2S)-2- (methoxymethyl)pyrrolidin-1-yl]-3- [(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5-c]pyridin-6- yl}-1,2,4- oxadiazol-5(4H)- one TFA 538 538 3.69 47

3-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-{2-[(1- methylethoxy) methyl]pyrrolidin- 1-yl}-3H-imidazo[4,5- c]pyridin-6-yl]- 1,2,4-oxadiazol- 5(4H)-one (enantiomer 2)TFA 566 566 3.70 1

3-{4-(5- chloropyridin-3- yl)-2-[(2S)-2- (difluoromethyl)pyrrolidin-1-yl]- 3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 544 5443.72 5

3-{4-(5- chloropyridin-3- yl)-2-(trans-2,3- dimethylmorpholin- 4-yl)-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one (racemic) TFA 538 538 3.73 6

3-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-(7- oxa-1- azaspiro[4.4]non- 1-yl)-3H- imidazo[4,5-c]pyridin-6-yl]- 1,2,4-oxadiazol- 5(4H)-one TFA 550 550 3.74 3

3-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-(8- oxa-1- azaspiro[4.5] dec-1-yl)-3H- imidazo[4,5-c]pyridin-6-yl]- 1,2,4-oxadiazol- 5(4H)-one TFA 564 564 3.75 1

3-{4-(5- chloropyridin-3- yl)-2-(trans-2,3- dimethylmorpholin- 4-yl)-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one (enantiomer 1) TFA 538 538 3.76 25

3-{4-(5- chloropyridin-3- yl)-2-(trans-2,3- dimethylmorpholin-4-yl)-3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (enantiomer 2) TFA 538538 3.77 10

3-{4-(5- chloropyridin-3- yl)-2- (hexahydro-2H- pyrano[4,3-b]pyridin-1(5H)- yl)-3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 564 5643.78 1

3-{4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-[2- (1H-1,2,3-triazol-5- yl)pyrrolidin-1- yl]-3H-imidazo[4,5-c] pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 561 5613.79 12

3-{4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-[2- (1-methyl-1H- 1,2,4-triazol-3- yl)pyrrolidin-1- yl]-3H-imidazo[4,5-c] pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 575 5753.80 21

3-{4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-[2- (1-methyl-1H- 1,2,4-triazol-5- yl)pyrrolidin-1- yl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 575 5753.81 <1

3-{4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl) methyl]-2-[(2S)-2-(1,3- thiazol-2- yl)pyrrolidin-1- yl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 577 577 3.82 2

3-{4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-[2- (3-methylisoxazol- 5-yl)pyrrolidin-1- yl]-3H-imidazo[4,5-c] pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 575 5753.83 11

3-{4-(5- chloropyridin-3- yl)-2-[2-(3,5- dimethylisoxazol-4-yl)pyrrolidin-1- yl]-3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 589 5893.84 1

3-{4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-[2- (3-methyl-1,2,4- oxadiazol-5- yl)pyrrolidin-1- yl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 576 5763.85 144

1-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-6-(5- oxo-4,5- dihydro-1,2,4- oxadiazol-3-yl)- 3H-imidazo[4,5-c]pyridin-2-yl]- N-ethyl-D- prolinamide TFA 565 565 3.86 11

(5R)-4-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-6-(5- oxo-4,5- dihydro-1,2,4- oxadiazol-3-yl)- 3H-imidazo[4,5-c]pyridin-2-yl]- 1,5- dimethylpiperazin- 2-one TFA 551 551 3.87 3

3-{4-(5- chloropyridin-3- yl)-2-[(2R)-5- methoxy-2- methylpiperidin-1-yl]-3-[(trans- 4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 552 552 3.88 8

3-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-(3- methyl-1,1- dioxidothio- morpholin-4-yl)- 3H-imidazo[4,5-c]pyridin-6-yl]- 1,2,4-oxadiazol- 5(4H)-one TFA 572 572 3.89 9

3-{4-(5- chloropyridin-3- yl)-2-(2- methoxy-7- azabicyclo[2.2.1]hept-7-yl)-3- [(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 550 550 3.90 <1

3-{4-(5- chloropyridin-3- yl)-2-[(2S,4R)-4- methoxy-2-(1- methylethyl)pyrrolidin-1-yl]-3- [(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 566 5663.91 1

3-{4-(5- chloropyridin-3- yl)-2-[(2S,4R)- 4-hydroxy-2-(1- methylethyl)pyrrolidin-1-yl]-3- [(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 552 5523.92 1

3-{4-(5- chloropyridin-3- yl)-2-[(2S,4R)-2- (fluoromethyl)-4-methoxypyrrolidin- 1-yl]-3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one 556 556 3.93353

3-{4-(5- chloropyridin-3- yl)-2-[(2R,4R)-2- (fluoromethyl)-4-methoxypyrrolidin- 1-yl]-3- [(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one 556 556 3.94 1

3-{4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl) methyl]-2-[methyl(2,2,2- trifluoroethyl) amino]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one TFA 536 536 3.95 26

3-(4-(5- chloropyridin-3- yl)-2-((trans-4- methoxytetrahydro-furan-3-yl)(methyl) amino)-3-((trans-4- methylcyclohexyl) methyl)-3H-imidazo[4,5- c]pyridin-6-yl)- 1,2,4-oxadiazol- 5(4H)-one (racemic) TFA554 554 3.96 13

3-{4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-[2- (1-methyl-1H- 1,2,3-triazol-4- yl)pyrrolidin-4- yl]-3H-imidazo[4,5-c] pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 575 5753.97 7

1-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-6-(5- oxo-4,5- dihydro-1,2,4- oxadiazol-3-yl)- 3H-imidazo[4,5-c]pyridin-2-yl]- N-ethyl-N- methyl-L- prolinamide TFA 579 579 3.98 1

3-{4-(5- chloropyridin-3- yl)-2-[(2- fluorophenyl) amino]-3-[(trans-4-methylcyclohexyl) methyl]-3H- imidazo[4,5-c] pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one 534 534 3.99 3

3-{4-(5- chloropyridin-3- yl)-2-[2-(1-ethyl- 1H-pyrazol-5-yl)pyrrolidin-1- yl]-3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 588 5883.100 7

3-{4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-[2- (1-methyl-1H- pyrazol-4- yl)pyrrolidin-1- yl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 574 5743.101 1

3-{4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-[2- (5-methyl-1,2,4- oxadiazol-3- yl)pyrrolidin-1- yl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 576 5763.102 <1

3-{4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-[2- (3-methyl-1,2,4- oxadiazol-5- yl)pyrrolidin-1- yl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (enantiomer 1)576 576 3.103 116

3-{4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-[2- (3-methyl-1,2,4- oxadiazol-5- yl)pyrrolidin-1- yl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (enantiomer 2)576 576 3.104 19

3-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-(6- oxa-1- azaspiro[3.3]hept- 1-yl)-3H- imidazo[4,5-c]pyridin-6-yl]- 1,2,4-oxadiazol- 5(4H)-one 522 522 3.105 9

3-{4-(5- choropyridin-3- yl)-2-[(2- methoxy-2- methylpropyl)(methyl)amino]- 3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 540 540 3.106 1

3-{4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-[2- (2-methyl-1,3- thiazol-4- yl)pyrrolidin-1- yl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 591 5913.107 41

3-{4-(5- chloropyridin-3- yl)-2-[(2- methoxyethyl) (methyl)amino]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one TFA 512 512 3.108 11

3-{4-(5- chloropyridin-3- yl)-2-[ethyl(2- methoxyethyl)amino]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 526 526 3.109 14

1-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl]-methyl]-6-(5- oxo-4,5- dihydro-1,2,4- oxadiazol-3-yl)- 3H-imidazo[4,5-c]pyridin-2-yl]- N,N-dimethyl-L- prolinamide TFA 565 565 3.110 9

3-{4-(5- chloropyridin-3- yl)-2-[(2- methoxyethyl) (propyl)amino]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one TFA 540 540 3.111 2

3-{4-(5- choropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-[(1- pyridin-2- ylethyl)amino]- 3H-imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 545 545 3.112 50

1-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-6-(5- oxo-4,5- dihydro-1,2,4- oxadiazol-3-yl)- 3H-imidazo[4,5-c]pyridin-2-yl]- N-ethyl-L- prolinamide TFA 565 565 3.113 2

3-{2-[(2S,5S)- 2,5- bis(methoxymethyl) pyrrolidin-1- yl]-4-(5-chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 582 5823.114 16

3-{4-(5- chloropyridin-3- yl)-2-[cis-4- methoxy-2- methylpiperidin-1-yl]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (racemic) 552 552 3.115 9

3-{4-(5- chloropyridin-3- yl)-2-[trans-4- methoxy-2- methylpiperidin-1-yl]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (racemic) 552 552 3.116 5

3-{4-(5- chloropyridin-3- yl)-2-[(trans-4- methoxy-2- methylpiperidin-1-yl]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (enantiomer 1) 552 552 3.11718

3-{4-(5- chloropyridin-3- yl)-2-[trans-4- methoxy-2- methylpiperidin-1-yl]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (enantiomer 2) 552 552 3.11813

3-{4-(5- chloropyridin-3- yl)-2-[cis-4- methoxy-2- methylpiperidin-1-yl]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (enantiomer 1) 552 552 3.11931

3-{4-(5- chloropyridin-2- yl)-2-[cis-4- methoxy-2- methylpiperidin-1-yl]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (enantiomer 2) 552 552 3.12032

(4aS,7aS)-4-[4- (5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-6-(5- oxo-4,5- dihydro-1,2,4- oxadiazol-3-yl)- 3H-imidazo[4,5-c]pyridin-2-yl]-1- methyloctahydro- 2H-cyclopenta[b] pyrazin-2-one 577577 3.121 9

4-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-6-(5- oxo-4,5- dihydro-1,2,4- oxadiazol-3-yl)- 3H-imidazo[4,5-c]pyridin-2-yl]- 5-ethyl-1- methylpiperazin- 2-one (racemic) 565 5653.122 6

4-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-6-(5- oxo-4,5- dihydro-1,2,4- oxadiazol-3-yl)- 3H-imidazo[4,5-c]pyridin-2-yl]- 5-ethyl-1- methylpiperazin- 2-one (enantiomer 1) 565565 3.123 25

4-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-6-(5- oxo-4,5- dihydro-1,2,4- oxadiazol-3-yl)- 3H-imidazo[4,5-c]pyridin-2-yl]- 5-ethyl-1- methylpiperazin- 2-one (enantiomer 2) 565565 3.124 29

3-{4-(5- chloropyridin-3- yl)-2- (hexahydro-2H- pyrano[4,3-b]pyridin-1(5H)- yl)-3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (enantiomer 1)564 564 3.125 8

3-{4-(5- chloropyridin-3- yl)-2- (hexahydro-2H- pyrano[4,3-b]pyridin-1(5H)- yl)-3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (enantiomer 2)564 564 3.126 250

benzyl (4aR,8aR)-1-[4- (5- chloropyridin-3- yl)-3-[(trans-4-methylcyclohexyl) methyl]-6-(5- oxo-4,5- dihydro-1,2,4- oxadiazol-3-yl)-3H-imidazo[4,5- c]pyridin-2- yl]octahydro- 6H-pyrido[3,4-b][1,4]oxazine- 6-carboxylate 699 699 3.127 512

3-{4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl) methyl]-2-[(4aR,8aR)- octahydro-1H- pyrido[3,4- b][1,4]oxazin-1- yl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 565 5653.128 129

3-{2- [(4aR,8aR)-6- benzyloctahydro- 1H-pyrido[3,4- b][1,4]oxazin-1-yl]-4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-3H- imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA655 655 3.129 14

3-{4-(5- chloropyridin-3- yl)-2-(2- hydroxy-7- azabicyclo[2.2.1]hept-7-yl)-3- [(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 536 536 3.130 14

3-{4-(5- chloropyridin-3- yl)-2-(2- methoxy-7- azabicyclo[2.2.1]hept-7-yl)-3- [(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (enantiomer 1) 550 5503.131 9

3-{4-(5- chloropyridin-3- yl)-2-(2- methoxy-7- azabicyclo[2.2.1]hept-7-yl)-3- [(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (enantiomer 2) 550 550 3.1321

3-{4-(5- chloropyridin-3- yl)-2-[(2S,4S)- 4-hydroxy-4- methyl-2-(1-methylethyl) pyrrolidin-1-yl]-3- [(trans-4- methylcyclohexyl)methyl]-3H- imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one 566566 3.133 3

3-{4-(5- chloropyridin-3- yl)-2-[(2S,4R)- 4-methoxy-2- (methoxymethyl)pyrrolidin-1-yl]- 3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 568 5683.134 28

3-{4-(5- chloropyridin-3- yl)-2-(3- hydroxyoctahydro-quinolin-1(2H)-yl)- 3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one(stereoisomer 1) TFA 578 578 3.135 3

3-{4-(5- chloropyridin-3- yl)-2-(3- hydroxyoctahydro-quinolin-1(2H)-yl)- 3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (stereoisomer2) TFA 578 578 3.136 <1

3-{4-(5- chloropyridin-3- yl)-2-(3- hydroxyoctahydro-quinolin-1(2H)-yl)- 3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (stereoisomer 3) TFA578 578 3.137 5

3-{4-(5- chloropyridin-3- yl)-2-(3- hydroxyoctahydro- quinolin-1(2H)-yl)-3- [(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (stereoisomer 4) TFA 578 5783.138 2

3-{4-(5- chloropyridin-3- yl)-2-[(2S,4R)- 4-methoxy-2-(1- methoxycyclo-propyl)pyrrolidin- 1-yl]-3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 594 5943.139 10

3-{4-(5- chloropyridin-3- yl)-2-[(2R,4R)- 4-methoxy-2-(1-methoxycyclopropyl) pyrrolidin-1-yl]-3- [(trans-4- methylcyclohexyl)methyl]-3H- imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA594 594 3.140 9

3-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-(3- methylthiomorpholin- 4-yl)-3H- imidazo[4,5-c]pyridin-6-yl]- 1,2,4-oxadiazol- 5(4H)-one (racemic) TFA 540 540 3.1411

3-{4-(5- chloropyridin-3- yl)-2-[(2S,4R)-2- (difluoromethyl)-4-methoxypyrrolidin- 1-yl]-3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 574 5743.142 1

3-{4-(5- chloropyridin-3- yl)-2-[(2S,4R)- 4-ethoxy-2- (fluoromethyl)pyrrolidin-1-yl]-3- [(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 570 5703.143 4

(4aR,7aR)-4-[4- (5-chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-6-(5- oxo-4,5- dihydro-1,2,4- oxadiazol-3-yl)- 3H-imidazo[4,5-c]pyridin-2-yl]-1- ethyloctahydro-2H- cyclopenta[b]pyrazin- 2-one TFA591 591 3.144 <1

3-{4-(5- chloropyridin-3- yl)-2-[(2S,4R)-4-(2- methoxyethoxy)-2-(1-methylethyl) pyrrolidin-1-yl]-3- [(trans-4- methylcyclohexyl)methyl]-3H- imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA610 610 3.145 1

3-{4-(5- chloropyridin-3- yl)-2-[(trans)-5,5- difluorohexahydro-cyclopenta[b][1,4] oxazin-4(4aH-yl]-3- [(trans-4- methylcyclohexyl)methyl]-3H- imidazo[4,5-c] pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one(racemic) TFA 586 586 3.146 1

3-{4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-[(trans)-3- methylhexahydro- cyclopenta[b][1,4]oxazin-4(4aH)-yl]- 3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol-5(4H)-one (racemic; major diastereomer) TFA 564 564 3.147 1

3-{4-(5- chloropyridin-3- yl)-2-[(2R,3R)- 3-ethyl-2- methylmorpholin-4-yl]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one 552 552 3.148 2

3-{4-(5- chloropyridin-3- yl)-2-[(trans)-6,6- difluorohexahydro-cyclopenta[b][1,4] oxazin-4(4aH)-yl]- 3-[(trans-4- methylcyclohexyl)methyl]-3H- imidazo[4,5-c] pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one(enantiomer 1) 586 586 3.149 130

3-{4-(5- chloropyridin-3- yl)-2-[(trans)-6,6- difluorohexahydro-cyclopenta[b][1,4] oxazin-4(4aH)-yl]- 3-[(trans-4- methylcyclohexyl)methyl]-3H- imidazo[4,5-c] pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one(enantiomer 2) 586 586 3.150 1

3-{4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl) methyl]-2-[(3R)-3-pyridin- 2-ylmorpholin- 4-yl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one 587 587 3.151 21

3-{4-(5- chloropyridin-3- yl)-2-(hexahydro- 4H,5H-pyrano[4,3-b][1,4]oxazin-4- yl)-3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one 566 566 3.15218

3-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-(2- methylhexahydro- 4H,5H-pyrano[4,3- b][1,4]oxazin-4-yl)-3H-imidazo[4,5- c]pyridin-6-yl]- 1,2,4-oxadiazol- 5(4H)-one(stereoisomer 1) 580 580 3.153 63

3-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-(2- methylhexahydro- 4H,5H-pyrano[4,3- b][1,4]oxazin-4-yl)-3H- imidazo[4,5- c]pyridin-6-yl]-1,2,4- oxadiazol-5(4H)- one(stereoisomer 2) 580 580 3.154 3

3-{4-(5- chloropyridin-3- yl)-2-[(trans)- hexahydro-4H- furo[3,4-b][1,4]oxazin-4-yl]-3- [(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (enantiomer 1) 552 552 3.155131

3-{4-(5- chloropyridin-3- yl)-2-[(trans)- hexahydro-4H- furo[3,4-b][1,4]oxazin-4- yl]-3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (enantiomer 2)552 552 3.156 1

3-{4-(5- chloropyridin-3- yl)-2-[(trans)-6- fluorohexahydro-cyclopenta[b] [1,4]oxazin- 4(4aH)-yl]-3- [(trans-4- methylcyclohexyl)methyl]-3H- imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one(stereoisomer 1) 568 568 3.157 113

3-{4-(5- chloropyridin-3- yl)-2-[(trans)-6- fluorohexahydro-cyclopenta[b] [1,4]oxazin- 4(4aH)-yl]-3- [(trans-4- methylcyclohexyl)methyl]-3H- imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one(stereoisomer 2) 568 568 3.158 4

3-{4-(5- chloropyridin-3- yl)-2-[(trans)-6- fluorohexahydro-cyclopenta[b] [1,4]oxazin- 4(4aH)-yl]-3- [(trans-4- methylcyclohexyl)methyl]-3H- imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one(stereoisomer 3) 568 568 3.159 48

3-{4-(5- chloropyridin-3- yl)-2-[(trans)-6- fluorohexahydro-cyclopenta[b] [1,4]oxazin- 4(4aH)-yl]-3- [(trans-4- methylcyclohexyl)methyl]-3H- imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one(stereoisomer 4) 568 568 3.160 80

3-{4-(5- chloropyridin-3- yl)-2- (hexahydro-2H- cyclopenta[b][1,4]oxazepin- 5(5aH)-yl)-3- [(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (enantiomer 1)564 564 3.161 1

3-{4-(5- chloropyridin-3- yl)-2- (hexahydro-2H- cyclopenta[b][1,4]oxazepin- 5(5aH)-yl)-3- [(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (enantiomer 2)564 564 3.162 17

3-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl) methyl]-2-(2,2,3- trimethylmorpholin- 4-yl)-3H- imidazo[4,5- c]pyridin-6-yl]-1,2,4-oxadiazol- 5(4H)-one (racemic) 552 552 3.163 3

3-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-(2- methyloctahydro- 4H-1,4- benzoxazin-4- yl)-3H-imidazo[4,5- c]pyridin-6-yl]- 1,2,4-oxadiazol- 5(4H)-one 578 578 3.164 5

3-{2- (benzylamino)- 4-(5- chloropyridin-3- yl)-3-[(trans-4-methylcyclohexyl) methyl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one 530 530 3.165 14

3-{4-(5- chloropyridin-3- yl)-2-[(2- methoxy-1- methylethyl)amino]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one 512 512 3.166 19

3-{2- [benzyl(methyl) amino]-4-(5- chloropyridin-3- yl)-3-[(trans-4-methylcyclohexyl) methyl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one 544 544 3.167 8

3-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-(2- methylhexahydro- cyclopenta[b] [1,4]oxazin- 4(4aH)-yl)-3H-imidazo[4,5- c]pyridin-6-yl]- 1,2,4-oxadiazol- 5(4H)-one(stereoisomer 1) 564 564 3.168 1

3-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-(2- methylhexahydro- cyclopenta[b][1,4] oxazin-4(4aH)-yl)-3H-imidazo[4,5- c]pyridin-6-yl]- 1,2,4-oxadiazol- 5(4H)-one(stereoisomer 2) 564 564 3.169 17

3-{4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl) methyl]-2-[(2R,3R)-2,3,6- trimethylmorpholin- 4-yl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (diastereomer 1) 522 5223.170 1

3-{4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl) methyl]-2-[(2R,3R)-2,3,6- trimethylmorpholin- 4-yl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (diastereomer 2) 552 5523.171 42

3-{4-(5- chloropyridin-3- yl)-2-[(2- methoxy-1- methylethyl)(methyl)amino]-3- [(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (racemic) 526 526 3.172 23

3-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl) methyl]-2-(pyridin-2- ylamino)-3H- imidazo[4,5- c]pyridin-6-yl]- 1,2,4-oxadiazol-5(4H)-one TFA 517 517 3.173 40

4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl) methyl]-2-(pyridin-2- ylamino)-3H- imidazo[4,5- c]pyridine-6- carboxylic acid TFA477 477 3.174 132

3-{4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-[methyl (phenyl)amino]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one TFA 530 530 3.175 86

4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl) methyl]-2-[methyl(phenyl) amino]-3H- imidazo[4,5- c]pyridine-6- carboxylic acidTFA 490 490 3.176 18

3-[4-(5- chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl) methyl]-2-(phenylamino)- 3H-imidazo[4,5- c]pyridin-6-yl]- 1,2,4-oxadiazol-5(4H)-one 516 516

Preparative Example 4.1 1-(trans-4-methylcyclohexyl)ethanone

Step 1: To a solution of trans-4-methylcyclohexanecarboxylic acid (100g, 0.70 mol) in DMF (1.2 L) were added HATU (294 g, 0.77 mol) and DIPEA(273 g, 2.1 mol) at room temperature. After stirring for 0.5 h, TLCshowed no starting material left (petroleum ether/ethyl acetate=5:1).Then N,O-dimethylhydroxylamine hydrochloride (75.5 g, 0.77 mol) wasadded slowly. The mixture was stirred at room temperature for 3 h. TLC(petroleum ether/ethyl acetate=5:1) showed the reaction was complete.The reaction was diluted with water and extracted with ethyl acetate.The organic layer was washed with water twice, washed with brine, driedover Na₂SO₄ and concentrated to give crudetrans-N-methoxy-N,4-dimethylcyclohexanecarboxamide, which was used forthe next step without further purification.

Step 2: MeMgBr (352 mL, 1.1 mol, 3 mol/L) was added dropwise slowly to astirred solution of trans-N-methoxy-N,4-dimethylcyclohexanecarboxamide(130 g, 0.7 mol) in THF (1.2 L) at 0° C. The mixture was stirred at roomtemperature for 2 hours. TLC showed no starting material (petroleumether/ethyl acetate=5:1) left. The mixture was cooled to 0-5° C., andquenched by the addition of saturated NH₄Cl (0.1 L) and H₂O (2 L). Themixture was extracted with ethyl acetate twice. The combined organiclayer was washed with brine and dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give crude1-(trans-4-methylcyclohexyl)ethanone, which was used for the next stepwithout further purification. ¹H NMR (400 MHz, CDCl₃) δ: 2.27-2.19 (m,1H), 2.10 (s, 3H), 1.90 (d, J=12.8 Hz, 2H), 1.70 (d, J=12.8 Hz, 2H),1.35-1.23 (m, 3H), 0.96-0.85 (m, 5H).

Preparative Example 4.2 tert-butyl(3-amino-2,6-dichloropyridin-4-yl)carbamate

Step 1: 2,6-dichloropyridin-4-amine (100 g, 0.617 mol) was added slowlyto conc. H₂SO₄ (415 mL) by portion while cooled with an ice bath. Themixture was cooled to 0° C., and nitric acid (250 mL) was added dropwiseat 0° C. The mixture was stirred at room temperature for 2 h. TLC(petroleum ether/ethyl acetate=2:1) showed the reaction was complete.The mixture was poured into crushed ice and stirred for 30 min. Theresulting precipitate was collected by filtration and washed with waterto give crude N-(2,6-dichloropyridin-4-yl)nitramide as a yellow solid,which was used for the next step without further purification.

Step 2: N-(2,6-dichloropyridin-4-yl)nitramide (205 g crude, 0.617 mol)was added carefully to conc. H₂SO₄ (800 mL) at room temperature. Thenthe reaction mixture was stirred at 80° C. for 2 h. TLC (Petroleumether/ethyl acetate=2:1) showed the reaction was complete. The mixturewas cooled to room temperature and poured into crushed ice. The mixturewas cooled to 0° C. and neutralized with NaOH and NH₄OH. The resultingprecipitate was collected by filtration and washed with water. Theresulting precipitate was dissolved in ethyl acetate, dried over Na₂SO₄and concentrated to give crude 2,6-dichloro-3-nitropyridin-4-amine,which was used for the next step without further purification. ¹H NMR(400 MHz, CDCl₃) δ: 7.64 (s, 2H), 6.86 (s, 1H).

Step 3: 2,6-dichloro-3-nitropyridin-4-amine (50 g, 0.24 mol) and (Boc)₂O(78.5 g, 0.36 mol) were dissolved in tetrahydrofuran (0.4 L). Then themixture was cooled to −70° C. NaHMDS in THF (725 mL, 0.725 mol, 1 mol/L)was added dropwise to the mixture. The resulting mixture was stirred for2 h at −70° C. TLC (petroleum/ethyl acetate=5:1) showed the reaction wascomplete. The mixture was poured into ice water and extracted with ethylacetate. The combined organic layers were washed with water and brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure togive crude tert-butyl (2,6-dichloro-3-nitropyridin-4-yl)carbamate as ayellow solid, which was used for the next step without furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ: 8.27 (s, 1H), 7.78 (s, 1H),1.38 (s, 9H)

Step 4: tert-Butyl (2,6-dichloro-3-nitropyridin-4-yl)carbamate (65 g,0.212 mol) was added to a mixture of Raney-Ni (12.5 g) in ethanol (1.5L) under H₂. The mixture was stirred at 50° C. for 3 h. TLC(petroleum/ethyl acetate=5:1) showed that most of the tert-butyl(2,6-dichloro-3-nitropyridin-4-yl)carbamate was consumed. The mixturewas filtered, and the filtrate was concentrated to give crude tert-butyl(3-amino-2,6-dichloropyridin-4-yl)carbamate, which was used for the nextstep without further purification. ¹H NMR (400 MHz, CDCl₃) δ: 7.84 (s,1H), 6.85 (s, 1H), 1.54 (s, 9H).

Preparative Example 4.34,6-dichloro-3-[1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine

Step 1: p-TsOH.H₂O (3.4 g, 0.018 mol) was added to a mixture oftert-butyl (3-amino-2,6-dichloropyridin-4-yl)carbamate (85 g, 0.306 mol)and 1-(trans-4-methylcyclohexyl)ethanone (64 g, 0.46 mol) in toluene(1.3 L). The mixture was heated to reflux with a Dean-Stark trap for 14h. TLC (petroleum/ethyl acetate=5:1) showed about 2/3 of tert-butyl(3-amino-2,6-dichloropyridin-4-yl)carbamate was consumed. The solventwas removed under reduced pressure. The residue was purified by columnchromatography (petroleum ether) to give crude tert-butyl(2,6-dichloro-3-((1-(trans-4-methylcyclohexyl)ethylidene)amino)pyridin-4-yl)carbamate.

Step 2: NaCNBH₃ (100 g, 1.59 mol) was added to a mixture of tert-butyl(2,6-dichloro-3-((1-(trans-4-methylcyclohexyl)ethylidene)amino)pyridin-4-yl)carbamate(80 g, 0.2 mol) and acetic acid (60 mL) in ethanol (1.2 L). The mixturewas heated to 50° C. for 4 h. TLC (petroleum ether/ethyl acetate=8:1)showed the reaction was complete. The reaction mixture was cooled down,poured into ice water, and then extracted with ethyl acetate. Thecombined organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated to give crude tert-butyl(2,6-dichloro-3-((1-(trans-4-methylcyclohexyl)ethyl)amino)pyridin-4-yl)carbamate,which was used for the next step without further purification.

Step 3: Crude tert-butyl(2,6-dichloro-3-((1-(trans-4-methylcyclohexyl)ethyl)amino)pyridin-4-yl)carbamate(70 g, 0.17 mol) was dissolved in a solution of HCl in dioxane (550 mL,4 mol/L). The mixture was heated to 50° C. for 12 h. TLC (petroleumether/ethyl acetate=5:1) showed the reaction was complete. White solidappeared. The solvent was removed under reduced pressure. The residuewas washed with methyl tertiary butyl ether to give crude2,6-dichloro-N³-(1-(trans-4-methylcyclohexyl)ethyl)pyridine-3,4-diamine,which was used for the next step without further purification. ¹H NMR(400 MHz, DMSO-d₆) δ: 6.63 (s, 1H), 3.16-3.13 (m, 1H), 1.84-1.76 (m,2H), 1.67 (bs, 2H), 1.39 (bs, 1H), 1.25 (bs, 1H), 1.10-0.96 (m, 5H),0.89-0.81 (m, 5H).

Step 4: A suspension of2,6-dichloro-N³-(1-(trans-4-methylcyclohexyl)ethyl)pyridine-3,4-diamine(35 g, 0.116 mol) in triethylorthoformate (200 mL, 1.16 mol) was stirredat 100° C. for 3 h. TLC (petroleum ether/ethyl acetate=3/1) showed thereaction was complete. The solvent was removed under reduced pressure.The residue was purified by column chromatography (petroleum ether/ethylacetate=10:1) to give the crude product, which was washed with a mixtureof petroleum ether/ethyl acetate=10:1 to afford4,6-dichloro-3-[1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine.¹H NMR (400 MHz, DMSO-d₆) δ: 8.85 (s, 1H), 7.86 (s, 1H), 4.98 (bs, 1H),1.76-1.67 (m, 3H), 1.58-1.56 (m, 4H), 1.23-1.20 (m, 2H), 1.07-0.99 (m,2H), 0.84-0.79 (m, 5H). MS ESI calc'd. for C₁₅H₁₉Cl₂N₃ [M+H]⁺ 312, found312.

Example 4.1 and Example 4.23-{4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(1R)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-oneand3-{4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(1S)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(diastereoisomer 1 and diastereoisomer 2)

Step 1: Racemic4,6-dichloro-3-[1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine(Preparative Example 4.3) (5 g, 16 mmol), 5-chloropyridine-3-boronicacid (2.77 g, 17.61 mmol), cesium carbonate (15.65 g, 48 mmol), and1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride (1.17 g,1.6 mmol) were combined in a flask that had been oven-dried and flushedwith nitrogen. Dioxane (43 mL) and water (10.6 mL) were added, and thevial was capped and heated to 90° C. for 3 hours. The reaction mixturewas cooled to room temperature, diluted with ethyl acetate, and washedwith water. The organic layer was washed with brine, dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel chromatography (0-100% ethyl acetate/hexanes,linear gradient) to afford racemic6-chloro-4-(5-chloropyridin-3-yl)-3-[1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine.MS ESI calc'd. for C₂₀H₂₂Cl₂N₄ [M+H]⁺ 389, found 389.

Step 2: In an oven-dried, nitrogen cooled flask were placedpalladium(II) acetate (286 mg, 1.27 mmol) and(R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (793 mg, 1.27 mmol).N,N-dimethylacetamide (76 mL) was added and degassed for three minuteswith nitrogen (sparge). Sulfuric acid (0.068 mL, 1.27 mmol) was addedand degassed for three minutes with nitrogen (sparge). The flask wassealed and heated to 80° C. for 30 minutes. The mixture was cooled toroom temperature and added to a separate nitrogen purged flaskcontaining racemic6-chloro-4-(5-chloropyridin-3-yl)-3-[1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine(4.96 g, 12.7 mmol), zinc cyanide (748 mg, 6.37 mmol), and zinc (83 mg,1.27 mmol). The flask was purged with nitrogen for five minutes andsealed and heated to 80° C. for 16 hours. The reaction mixture wascooled to room temperature, filtered, diluted with ethyl acetate, andwashed with water and brine. The organic layer was dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel chromatography (0-100% ethyl acetate/hexanes,linear gradient) to afford racemic4-(5-chloropyridin-3-yl)-3-[1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ESI calc'd. for C₂₁H₂₂ClN₅ [M+H]⁺ 380, found 380.

Step 3: N-bromosuccinimide (4.07 g, 22.9 mmol) was added to a roomtemperature solution of racemic4-(5-chloropyridin-3-yl)-3-[1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(4.14 g, 7.63 mmol) stirring in degassed chloroform (38 mL). Thereaction was heated to reflux for 1.5 hours. The mixture was cooled toroom temperature, diluted with dichloromethane, and washed withsaturated aqueous sodium thiosulfate (2×) and brine. The organic layerwas dried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by silica gel chromatography (0-80%ethyl acetate/hexanes, linear gradient) to afford racemic2-bromo-4-(5-chloropyridin-3-yl)-3-[1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.The racemic material was then purified by chiral supercritical fluidchromatography (Chiralpak IB, 21×250 mm, 25% methanol in CO₂) to afford2-bromo-4-(5-chloropyridin-3-yl)-3-[(1S)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrileand2-bromo-4-(5-chloropyridin-3-yl)-3-[(1R)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.Faster eluting enantiomer 1: MS ESI calc'd. for C₂₁ H_(2i)BrClN₅ [M+H]⁺458, found 458. Slower eluting enantiomer 2: MS ESI calc'd. for C₂₁H₂₁BrClN₅ [M+H]⁺ 458, found 458.

Alternatively, racemic4-(5-chloropyridin-3-yl)-3-[1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Step 2) was resolved into its enantiomers as described in PreparativeExample 15.1 and brominated using the conditions described above orusing the alternative conditions (disodium hydrogen phosphate and1,3-dibromo-5,5-dimethylhydantoin in THF at 35° C., described in Example2.1, Step 1 and Preparative Example 3.1, Step 3) to afford2-bromo-4-(5-chloropyridin-3-yl)-3-[(1S)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrileand2-bromo-4-(5-chloropyridin-3-yl)-3-[(1R)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.

Step 4: To a vial was added faster eluting enantiomer 12-bromo-4-(5-chloropyridin-3-yl)-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(150 mg, 0.327 mmol), (4aR,7aR)-octahydrocyclopenta[b][1,4]oxazine (83mg, 0.654 mmol), potassium fluoride (95 mg, 1.64 mmol), DMSO (1 mL), andN,N-diisopropylethylamine (0.286 mL, 1.64 mmol). The vial was sealed andheated to 100° C. for 16 hours. The reaction mixture was cooled to roomtemperature, diluted with ethyl acetate, and washed with water and thenbrine. The organic layer was dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (0-100% ethyl acetate/hexanes, linear gradient) toafford4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(1RorS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ESI calc'd. for C₂₈H₃₃ClN₆O [M+H]⁺ 505, found 505.

Step 5: Hydroxylamine hydrochloride (27.2 mg, 0.39 mmol), sodiumbicarbonate (49.4 mg, 0.59 mmol), and water (0.392 mL) were combined ina vial and stirred for 15 minutes. This solution was added to a vialcontaining4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(1RorS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(99 mg, 0.196 mmol), dissolved in ethanol (0.915 mL). The mixture wassealed and heated at 100° C. for 1 hour. The reaction was cooled to roomtemperature, quenched with water, and extracted with ethyl acetate (2×).The combined organic layers were dried over sodium sulfate, filtered,and concentrated to afford4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-N-hydroxy-3-[(1RorS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide.MS ESI calc'd. for C₂₈H₃₆ClN₇O₂ [M+H]⁺ 538, found 538.

Step 6: To a solution of4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-N-hydroxy-3-[(1RorS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide(105 mg, 0.195 mmol), and 1,1′-carbonyldiimidazole (34.8 mg, 0.215 mmol)dissolved in acetonitrile (1.9 mL) was added1,8-diazabicyclo[5.4.0]undec-7-ene (0.117 mL, 0.781 mmol). The reactionmixture was stirred at room temperature for 1 hour. The reaction waswashed with water and extracted with dichloromethane. The organic layerwas dried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by silica gel chromatography (0-10%methanol/dichloromethane, and then 0-100% ethyl acetate/hexanes, lineargradient) to afford3-{4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(1RorS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one.MS ESI calc'd. for C₂₉H₃₄ClN₇O₃ [M+H]⁺ 564, found 564. ¹H NMR (500 MHz,DMSO-d₆) δ 12.90 (s, 1H), 8.92 (d, J=1.7, 1H), 8.81 (d, J=2.4, 1H), 8.45(t, J=2.1, 1H), 8.14 (s, 1H), 4.04-3.93 (m, 1H), 3.76 (dd, J=9.8, 11.8,1H), 3.61 (s, 1H), 3.45 (q, J=7.8, 2H), 3.16-3.05 (m, 1H), 2.74 (dd,J=9.5, 12.0, 1H), 2.11 (s, 1H), 1.94-1.85 (m, 1H), 1.71-1.64 (m, 2H),1.63-1.48 (m, 5H), 1.31-1.16 (m, 2H), 1.15-1.05 (m, 1H), 0.98 (broad,1H), 0.92 (d, J=6.5, 1H), 0.87-0.72 (m, 2H), 0.69 (d, J=6.5, 3H),0.55-0.40 (m, 1H), 0.35-0.20 (m, 1H), 0.18-0.10 (m, 1H).

Diastereoisomer 2,3-{4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(1SorR)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one,was obtained using the same chemistry as described in steps 4-6,starting with slower eluting enantiomer 2 produced in Step 3 above. MSESI calc'd. for C₂₉H₃₄ClN₇O₃ [M+H]⁺ 564, found 564. ¹H NMR (500 MHz,DMSO-d₆) δ 12.86 (s, 1H), 8.83 (d, J=2.4, 1H), 8.75 (d, J=1.6, 1H), 8.30(t, J=2.0, 1H), 8.13 (s, 1H), 4.03-3.91 (m, 2H), 3.77 (dd, J=9.5, 11.8,1H), 3.47 (dd, J=9.5, 17.7, 1H), 3.06 (dd, J=8.0, 19.3, 2H), 2.89 (dd,J=9.2, 12.0, 1H), 1.97 (s, 1H), 1.91-1.81 (m, 1H), 1.70-1.43 (m, 6H),1.39-1.31 (m 1H), 1.24-1.14 (m, 4H), 1.11-0.96 (m, 1H), 0.92 (d, J=6.5,1H), 0.86-0.77 (m, 1H), 0.74 (d, J=6.5, 3H), 0.63-0.43 (m, 3H).

The following compounds in Table 4 (other than Example 4.1 and 4.2) wereprepared using procedures which were analogous to those described above.

TABLE 4 FRET IC₅₀ [M + H]⁺ [M + H]⁺ Ex. (nM) Structure Chemical NameSalt Calc'd Obsv'd 4.1 2

3-{4-(5- chloropyridin-3-yl)- 2-[(4aR,7aR)- hexahydrocyclo-penta[b][1,4]oxazin- 4(4aH)-yl]-3-[(1R or S)-1-(trans-4-methylcyclohexyl) ethyl]-3H- imidazo[4,5-c] pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one (diastereoisomer 1) TFA 564 564 4.2 1

3-{4-(5- chloropyridin-3-yl)- 2-[(4aR,7aR)- hexahydrocyclopenta[b][1,4]oxazin- 4(4aH)-yl]-3-[(1S or R)-1-(trans-4- methylcyclohexyl)ethyl]-3H- imidazo[4,5-c] pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one(diastereoisomer 2) TFA 564 564 4.3 3

3-(4-(5- chloropyridin-3-yl)- 3-(1-(trans-4- methylcyclohexyl)ethyl)-2-((R)-3- methylmorpholino)- 3H-imidazo[4,5-c] pyridin-6-yl)-1,2,4-oxadiazol- 5(4H)-one (diastereoisomer 1) TFA 538 538 4.4 1

3-(4-(5- chloropyridin-3-yl)- 3-(1-(trans-4- methylcyclohexyl)ethyl)-2-((R)-3- methylmorpholino)- 3H-imidazo[4,5-c] pyridin-6-yl)-1,2,4-oxadiazol- 5(4H)-one (diastereoisomer 2) TFA 538 538 4.5 4

(5R)-4-[4-(5- chloropyridin-3-yl)- 3-[1-(trans-4- methylcyclohexyl)ethyl]-6-(5-oxo-4,5- dihydro-1,2,4- oxadiazol-3-yl)-3H- imidazo[4,5-c]pyridin-2-yl]-1,5- dimethylpiperazin- 2-one (diastereoisomer 1) TFA 565565 4.6 13

(5R)-4-[4-(5- chloropyridin-3-yl)- 3-[1-(trans-4- methylcyclohexyl)ethyl]-6-(5-oxo-4,5- dihydro-1,2,4- oxadiazol-3-yl)-3H- imidazo[4,5-c]pyridin-2-yl]-1,5- dimethylpiperazin- 2-one (diastereoisomer 2) TFA 565565 4.7 1

3-{4-(5- chloropyridin-3-yl)- 2-[(2S,4R)-2- (fluoromethyl)-4-methoxypyrrolidin- 1-yl]-3-[1-(trans-4- methylcyclohexyl) ethyl]-3H-imidazo[4,5-c] pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one(diastereoisomer 1) TFA 570 570 4.8 1

3-{4-(5- chloropyridin-3-yl)- 2-[(2S,4R)-2- (fluoromethyl)-4-methoxypyrrolidin- 1-yl]-3-[1-(trans-4- methylcyclohexyl) ethyl]-3H-imidazo[4,5-c] pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one(diastereoisomer 2) TFA 570 570 4.9 1

3-{4-(5- chloropyridin-3-yl)- 2-[(2S,4R)-4- hydroxy-2-(propan-2-yl)pyrrolidin-1-yl]- 3-[1-(trans-4- methylcyclohexyl) ethyl]-3H-imidazo[4,5-c] pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one(diastereoisomer 1) TFA 566 566 4.10 1

3-{4-(5- chloropyridin-3-yl)- 2-[(2S,4R)-4- hydroxy-2-(propan-2-yl)pyrrolidin-1-yl]- 3-[1-(trans-4- methylcyclohexyl) ethyl]-3H-imidazo[4,5-c] pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one(diastereoisomer 2) TFA 566 566 4.11 3

3-{4-(5- chloropyridin-3-yl)- 2-[(2R,4R)-4- methoxy-2-methylpyrrolidin-1- yl]-3-[1-(trans-4- methylcyclohexyl) ethyl]-3H-imidazo[4,5-c] pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one(diastereomer 1) TFA 552 552 4.12 4

3-{4-(5- chloropyridin-3-yl)- 2-[(2R,4R)-4- hydroxy-2-methylpyrrolidin-1- yl]-3-[1-(trans-4- methylcyclohexyl) ethyl]-3H-imidazo[4,5-c] pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one(diastereomer 1) TFA 538 538 4.13 3

3-{4-(5- chloropyridin-3-yl)- 2-[(2R,4R)-4- hydroxy-2-methylpyrrolidin-1- yl]-3-[1-(trans-4- methylcyclohexyl) ethyl]-3H-imidazo[4,5-c] pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (diastereomer2) TFA 538 538 4.14 2

3-{4-(5- chloropyridin-3-yl)- 2-[(2R,4R)-4- methoxy-2-methylpyrrolidin-1- yl]-3-[1-(trans-4- methylcyclohexyl) ethyl]-3H-imidazo[4,5-c] pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (diastereomer2) TFA 552 552

Preparative Example 5.13-(4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-2-(R)-2-methylpiperazin-1-yl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one

Step 1: To a microwave vial was added (R)-tert-butyl3-methylpiperazine-1-carboxylate (purchased from Astatech) (180 mg,0.899 mmol),2-bromo-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile(200 mg, 0.450 mmol, Preparative Example 3.1), potassium fluoride (78mg, 1.349 mmol), DMSO (1 ml) and DIEA (0.236 ml, 1.349 mmol). Thereaction vial was capped and heated to 100° C. overnight. The mixturewas cooled to room temperature and diluted with EtOAc. The mixture waswashed with water and brine, then dried over sodium sulfate, filtered,and concentrated. The residue was purified by column chromatography onsilica gel, eluting with EtOAc/isohexane to give (R)-tert-butyl4-(4-(5-chloropyridin-3-yl)-6-cyano-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-2-yl)-3-methylpiperazine-1-carboxylate.MS ESI calc'd. for C₃₀H₃₈ClN₇O₂ [M+H]⁺ 564, found 564.

Step 2: Using a procedure analogous to that described in Example 2.1(Step 5), and starting with (R)-tert-butyl4-(4-(5-chloropyridin-3-yl)-6-cyano-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-2-yl)-3-methylpiperazine-1-carboxylate,(R)-tert-butyl4-(4-(5-chloropyridin-3-yl)-6-(N′-hydroxycarbamimidoyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-2-yl)-3-methylpiperazine-1-carboxylatewas prepared. MS ESI calc'd. for C₃₀H₄₁ClN₈O₃ [M+H]⁺ 597, found 597.

Step 3: Using a procedure analogous to that described in Example 2.1(Step 6), and starting with (R)-tert-butyl4-(4-(5-chloropyridin-3-yl)-6-(N′-hydroxycarbamimidoyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-2-yl)-3-methylpiperazine-1-carboxylate,(R)-tert-butyl4-(4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-3-methylpiperazine-1-carboxylatewas prepared. MS ESI calc'd. for C₃₁H₃₉ClN₈O₄ [M+H]⁺ 623, found 623.

Step 4: HCl solution in 1,4-Dioxane (4.0 M, 1.0 ml, 4.0 mmol) was addedto a stirred solution of (R)-tert-butyl4-(4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-3-methylpiperazine-1-carboxylate(164 mg, 0.263 mmol) in 1,4-dioxane (1 ml) at room temperature, and themixture was stirred at room temperature overnight. The solvent wasevaporated under reduced pressure to give3-(4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-2-(R)-2-methylpiperazin-1-yl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one(HCl salt). MS ESI calc'd. for C₂₆H₃₁ClN₈O₂ [M+H]+ 523, found 523.

Preparative Example 5.2 (4aR,7aR)-octahydro-1H-cyclopenta[b]pyrazine

To a cooled (0° C.) solution of(4aR,7aR)-octahydro-2H-cyclopenta[b]pyrazin-2-one (prepared in analogyto Example 3.120, Steps 1-3) (570 mg, 4.07 mmol) in THF (27 mL) wasadded dropwise LAH (4.07 mL of a 2.0M solution in THF, 8.14 mmol) over 5minutes. After the addition was complete, the mixture was capped with areflux condenser and heated to 65° C. for 14 hours. The resultingmixture was then cooled to room temperature and carefully quenched bythe addition of sodium sulfate decahydrate (1.3 g). The reaction mixturewas filtered through Celite®, and the filter cake was washed with ethylacetate. The combined filtrate was dried over magnesium sulfate,filtered, evaporated under reduced pressure and dried in vacuo to give(4aR,7aR)-octahydro-1H-cyclopenta[b]pyrazine. ¹H NMR (500 MHz, DMSO-d₆)δ 2.75-2.69 (m, 2H), 2.55-2.50 (m, 2H), 2.13-2.07 (m, 4H), 1.66-1.59 (m,2H), 1.57-1.51 (m, 2H), 1.22-1.12 (m, 2H).Example 5.13-(2-((R)-4-acetyl-2-methylpiperazin-1-yl)-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one

Acetic acid (6.73 mg, 0.112 mmol), N,N-diisopropylethylamine (29.0 mg,0.224 mmol) and HATU (42.6 mg, 0.112 mmol) were added to a stirred,cooled 0° C. solution of3-(4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-2-((R)-2-methylpiperazin-1-yl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one(HCl salt, 31.3 mg, 0.056 mmol) in DMF (1 ml), and the mixture wasstirred at room temperature overnight. The reaction mixture wasconcentrated under reduced pressure. The residue was purified bypreparative Reverse phase HPLC(C-18), eluting withacetonitrile/water+0.1% TFA, to give3-(2-((R)-4-acetyl-2-methylpiperazin-1-yl)-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one,TFA salt. MS ESI calc'd. for C₂₈H₃₃ClN₈O₃ [M+H]⁺ 565, found 565. ¹H NMR(500 MHz, DMSO-d₆) δ 12.88 (br s, 1H), 8.96 (d, J=1.8 Hz, 1H), 8.81 (d,J=2.3 Hz, 1H), 8.50 (s, 1H), 7.99 (d, J=1.8 Hz, 1H), 4.00-3.57 (m, 5H),3.53-3.16 (m, 4H), 2.05 (d, J=22.2 Hz, 3H), 1.38-1.32 (m, 2H), 1.20-1.12(m, 3H), 1.04-0.87 (m, 2H), 0.67-0.50 (m, 7H), 0.44-0.33 (m, 2H).

Example 5.53-(4-(5-chloropyridin-3-yl)-2-((2R,6R)-2,6-dimethyl-4-(methylsulfonyl)piperazin-1-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one

To a reaction vessel was added3-(4-(5-chloropyridin-3-yl)-2-(2R,6R)-2,6-dimethylpiperazin-1-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one(prepared in the same manner as Preparative Example 5.1, starting with2-bromo-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile,Preparative Example 3.1, and tert-butyl(3R,5R)-3,5-dimethylpiperazine-1-carboxylate, purchased from Enamine,0.025 g, 0.047 mmol) suspended in DMF (1.0 mL). To the reaction was thenadded methanesulfonyl chloride (0.011 g, 0.093 mmol). The reaction wasallowed to stir at ambient temperature for 2 hours. The reaction waspassed through a syringe filter, and the filtrate was purified byreverse phase preparative HPLC (0:100 to 95:5 acetonitrile:water: 0.1%v/v TFA modifier) to afford3-(4-(5-chloropyridin-3-yl)-2-(2R,6R)-2,6-dimethyl-4-(methylsulfonyl)piperazin-1-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one,TFA salt. MS ESI calc'd. for C₂₈H₃₆ClN₈O₄S [M+H]⁺ 615, found 615. ¹H NMR(600 MHz, DMSO) δ 8.94 (d, J=1.7, 1H), 8.80 (d, J=2.3, 1H), 8.47 (s,1H), 8.11 (s, 1H), 3.81 (m, 3H), 3.70 (m, 1H), 2.92 (s, 3H), 1.36 (m,3H), 1.05 (m, 8H), 0.80 (m, 1H), 0.75 (m, J=6.5, 8H), 0.50 (m, 1H), 0.33(m, 2H).

Example 5.6 (3R,5R)-ethyl4-(4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-3,5-dimethylpiperazine-1-carboxylate

To a reaction vessel was added ethanol (0.009 g, 0.195 mmol), DMSO (0.14mL), DIEA (0.065 mL, 0.37 mmol) and N,N′-Disuccinimidyl carbonate (0.047g, 0.18 mmol). The reaction vial was sealed and allowed to stir for 12hours at ambient temperature. To the reaction was then added3-(4-(5-chloropyridin-3-yl)-2-((2R,6R)-2,6-dimethylpiperazin-1-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one(prepared in the same manner as Preparative Example 5.1, starting with2-bromo-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile,Preparative Example 3.1, and tert-butyl(3R,5R)-3,5-dimethylpiperazine-1-carboxylate, purchased from Enamine;0.015 g, 0.028 mmol) and DMSO (0.14 mL). The reaction vial was sealedand allowed to stir for 12 hours at ambient temperature. The reactionwas passed through a syringe filter, and the filtrate was purified byreverse phase preparative HPLC (0:100 to 95:5 acetonitrile:water: 0.1%v/v TFA modifier) to afford (3R,5R)-ethyl4-(4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-3,5-dimethylpiperazine-1-carboxylate,TFA salt. MS ESI calc'd. for C₃₀H₃₇ClN₈O₄ [M+H]⁺ 609, found 609. ¹H NMR(500 MHz, DMSO-d₆): δ 12.89 (s, 1H), 8.96 (s, 1H), 8.82 (s, 1H), 8.49(s, 1H), 8.12 (s, 1H), 4.03-4.10 (m, 2H), 3.84-3.89 (m, 2H), 3.71 (s,4H), 3.60-3.63 (m, 2H), 1.37 (dd, J=28.9, 12.7 Hz, 2H), 1.19 (t, J=7.1Hz, 3H), 0.99-1.05 (m, 7H), 0.80-0.90 (m, 1H), 0.65-0.72 (m, 6H), 0.52(d, J=12.3 Hz, 1H), 0.36 (m, 2H).

Example 5.7(3R,5R)-4-(4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-N-ethyl-3,5-dimethylpiperazine-1-carboxamide

To a reaction vessel was added3-(4-(5-chloropyridin-3-yl)-2-(2R,6R)-2,6-dimethylpiperazin-1-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one(prepared in the same manner as Preparative Example 5.1, starting with2-bromo-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile,Preparative Example 3.1, and tert-butyl(3R,5R)-3,5-dimethylpiperazine-1-carboxylate, purchased from Enamine;0.015 g, 0.028 mmol), DMF (0.5 mL), DIEA (0.009 g, 0.052 mmol) andisocyanatoethane (0.0013 mL, 0.026 mmol). The reaction vial was sealedand allowed to stir at ambient temperature for 2 hours. The reaction wasdiluted with DMSO (0.5 mL) and passed through a syringe filter. Thefiltrate was purified by reverse phase preparative HPLC (0:100 to 95:5acetonitrile:water/0.1% v/v TFA modifier) to afford(3R,5R)-4-(4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-N-ethyl-3,5-dimethylpiperazine-1-carboxamide,TFA salt. MS ESI calc'd. for C₃₀H₃₈ClN₉O₃ [M+H]⁺ 608, found 608. ¹H NMR(500 MHz, DMSO-d₆) δ 12.88 (s, 1H), 8.96 (s, 1H), 8.82 (s, 1H), 8.49 (d,1H), 8.16 (d, 1H), 6.58 (s, 1H), 3.91 (m, 1H), 3.67 (m, 4H), 3.19 (m,3H), 1.38 (dd, 2H), 1.01 (m, 11H), 0.83 (m, 1H), 0.67 (m, 7H), 0.53 (m,1H), 0.36 (m, 2H).

Example 5.193-{2-[(4aR,7aR)-4-acetyloctahydro-1H-cyclopenta[b]pyrazin-1-yl]-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one

Step 1: To a microwave vial was added(4aR,7aR)-octahydro-1H-cyclopenta[b]pyrazine (Preparative Example 5.2,295 mg, 2.338 mmol),2-bromo-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Preparative Example 3.1, 800 mg, 1.799 mmol), potassium fluoride (209mg, 3.60 mmol), DMSO (8 ml), and DIEA (0.942 ml, 5.40 mmol). Thereaction vial was capped and heated to 100° C. overnight. The mixturewas then cooled to room temperature and diluted with EtOAc. The solutionwas washed with water and brine, dried over sodium sulfate, filtered,and concentrated to give crude4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(4aR,7aR)-octahydro-1H-cyclopenta[b]pyrazin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ESI calc'd. for C₂₇H₃₂ClN₇ [M+H]⁺ 490, found 490.

Step 2: Acetic acid (60.7 mg, 1.01 mmol), N,N-diisopropylethylamine (174mg, 1.348 mmol) and HATU (513 mg, 1.348 mmol) were added to4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(4aR,7aR)-octahydro-1H-cyclopenta[b]pyrazin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(177 mg, 0.33 mmol) in DMSO (1.5 ml), and the mixture was stirred atroom temperature overnight. The reaction was then diluted with EtOAc,washed with water and brine, dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel, eluting with EtOAc/isohexane to give2-[(4aR,7aR)-4-acetyloctahydro-1H-cyclopenta[b]pyrazin-1-yl]-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ESI calc'd. for C₂₉H₃₄ClN₇O [M+H]+ 532, found 532.

Step 3 & 4: Using a procedure analogous to that described in Example 2.1(Steps 5 and 6), and starting with2-[(4aR,7aR)-4-acetyloctahydro-1H-cyclopenta[b]pyrazin-1-yl]-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile,3-{2-[(4aR,7aR)-4-acetyloctahydro-1H-cyclopenta[b]pyrazin-1-yl]-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(TFA salt) was prepared. MS ESI calc'd. for C₃₀H₃₅ClN₈O₃ [M+H]+ 591,found 591. ¹H NMR (500 MHz, DMSO-d6) δ 12.86 (s, 1H), 8.96 (d, J=1.8 Hz,1H), 8.80 (d, J=2.4 Hz, 1H), 8.48 (t, J=2.1 Hz, 1H), 7.97 (s, 1H), 3.90(m, 2H), 3.78 (dd, J=14.5, 9.8 Hz, 2H), 3.52-3.61 (m, 4H), 2.02 (s, 3H),1.68 (m, 3H), 1.36 (m, 2H); 1.15 (m, 1H), 1.02-1.04 (m, 1H), 0.92-0.94(m, 1H), 0.66-0.67 (m, 7H), 0.38-0.48 (m, 4H).

The following compounds in Table 5 (other than Examples 5.1, 5.5, 5.6,5.7, and 5.19) were prepared using procedures that were analogous tothose described above.

TABLE 5 FRET IC₅₀ [M + H]+ [M + H]+ Ex. (nM) Structure Chemical NameSalt Calc'd Obsv'd 5.1  6

3-{2-[(2R)-4-acetyl-2- methylpiperazin-1-yl]- 4-(5-chloropyridin-3-yl)-3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one TFA 565 565 5.2  5

3-{4-(5-chloropyridin- 3-yl)-2-[(2R)-4- (cyclopropylcarbonyl)-2-methylpiperazin-1- yl]-3-[(trans-4- methylcyclohexyl)methyl]-3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one TFA 591 5915.3  1

3-{2-[(2R,6R)-4- acetyl-2,6- dimethylpiperazin-1-yl]-4-(5-chloropyridin-1- 3-yl)-3-[(trans-4- methylcyclohexyl)methyl]-3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4- oxadiazol-5(H)-one TFA 579 5795.4  1

3-{4-(5-chloropyridin- 3-yl)-2-[(2R,6R)-4- (cyclopropylcarbonyl)-2,6-dimethylpiperazin- 1-yl]-3-[(trans-4- methylcyclohexyl)methyl]-3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one TFA605 605 5.5  3

3-{4-(5-chloropyridin- 3-yl)-2-[(2R,6R)-2,6- dimethyl-4-(methylsulfonyl)piperazin- 1-yl]-3-[(trans-4- methylcyclohexyl)methyl]-3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one TFA 615 6155.6  2

ethyl (3R,5R)-4-[4-(5- chloropyridin-3-yl)-3- [(trans-4-methylcyclohexyl)methyl]- 6-(5-oxo-4,5- dihydro-1,2,4-oxadiazol-3-yl)-3H- imidazo[4,5-c]pyridin- 2-yl]-3,5-dimethylpiperazine-1- carboxylate TFA 609 609 5.7  3

(3R,5R)-4-[4-(5- chloropyridin-3-yl)-3- [(trans-4- methylcyclohexyl)methyl]-6-(5-oxo-4,5- dihydro-1,2,4- oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin- 2-yl]-N-ethyl-3,5- dimethylpiperazine-1-carboxamide TFA 608 608 5.8  3

3-{4-(5-chloropyridin- 3-yl)-2-[(2R,6R)-2,6- dimethyl-4-propanoylpiperazin-1- yl]-3-[(trans-4- methylcyclohexyl)methyl]-3H-imidazo[4,5-c] pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one TFA 593 5935.9  1

3-{4-(5-chloropyridin- 3-yl)-2-[(2R,6R)-4- (cyclobutylcarbonyl)-2,6-dimethylpiperazin- 1-yl]-3-[(trans-4- methylcyclohexyl)methyl]-3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one TFA 619 6195.10  3

3-{2-[(2R,6R)-4- butanoyl-2,6- dimethylpiperazin-1-yl]-4-(5-chloropyridin- 3-yl)-3-[(trans-4- methylcyclohexyl)methyl]-3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one TFA 607 6075.11  2

methyl (3R,5R)-4-[4- (5-chloropyridin-3-yl)- 3-[(trans-4-methylcyclohexyl)methyl]- 6-(5-oxo-4,5- dihydro-1,2,4-oxadiazol-3-yl)-3H- imidazo[4,5-c]pyridin- 2-yl]-3,5-dimethylpiperazine-1- carboxylate TFA 595 595 5.12  3

1-methylethyl (3R,5R)-4-[4-(5- chloropyridin-3-yl)-3- [(trans-4-methylcyclohexyl)methyl]- 6-(5-oxo-4,5- dihydro-1,2,4-oxadiazol-3-yl)-3H- imidazo[4,5-c]pyridin- 2-yl]-3,5-dimethylpyrazine-1- carboxylate TFA 623 623 5.13  2

(3R,5R)-4-[4-(5- chloropyridin-3-yl)-3- [(trans-4-methylcyclohexyl)methyl]- 6-(5-oxo-4,5- dihydro-1,2,4-oxadiazol-3-yl)-3H- imidazo[4,5-c]pyridin- 2-yl]-3,5-dimethyl-N-propylpiperazine-1- carboxamide TFA 622 622 5.14  3

(3R,5R)-4-[4-(5- chloropyridin-3-yl)-3- [(trans-4-methylcyclohexyl)methyl]- 6-(5-oxo-4,5- dihydro-1,2,4-oxadiazol-3-yl)-3H- imidazo[4,5-c]pyridin- 2-yl]-3,5-dimethyl-N-(1-methylethyl)piperazine- 1-carboxamide TFA 622 622 5.15 82

3-{2-(4-acetyl-2,3- dimethylpiperazin-1- yl)-4-(5-chloropyridin-3-yl)-3-[(trans-4- methylcyclohexyl)methyl]- 3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one TFA 579 579 5.16 68

3-{4-(5-chloropyridin- 3-yl)-2-[4- (cyclopropylcarbonyl)-2,3-dimethylpiperazin- 1-yl]-3-[(trans-4- methylcyclohexyl)methyl]-3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one TFA 605 6055.17  3

3-{4-(5-chloropyridin- 3-yl)-2-[(2R,6R)-2,6- dimethyl-4-(2-methylpropanoyl)piperazin- 1-yl]-3-[(trans-4- methylcyclohexyl)methyl]-3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one TFA 607 6075.18  5

3-{4-(5-chloropyridin- 3-yl)-2-[(4aR,7aR)-4- (cyclopropylcarbonyl)octahydro-1H- cyclopenta[b]pyrazin- 1-yl]-3-[(trans-4-methylcyclohexyl)methyl]- 3H-imidazo[4,5-c] pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one TFA 617 617 5.19  4

3-{2-[(4aR,7aR)-4- acetyloctahydro-1H- cyclopenta[b]pyrazin- 1-yl]-4-(5-chloropyridin-3-yl)-3- [(trans-4- methylcyclohexyl)methyl]-3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one TFA 591 5915.20  3

3-{4-(5-chloropyridin- 3-yl)-2-[(4aR,7aR)-4- (difluoroacetyl)octahydro-1H-cyclopenta[b]pyrazin- 1-yl]-3-[(trans-4- methylcyclohexyl)methyl]-3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one TFA 627 6275.21  5

3-{4-(5-chloropyridin- 3-yl)-2-[(4aR,7aR)-4- (cyclobutylcarbonyl)octahydro-1H- cyclopenta[b]pyrazin- 1-yl]-3-[(trans-4-methylcyclohexyl)methyl]- 3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one TFA 631 631 5.22  1

(3R,5R)-4-[4-(5- chloropyridin-3-yl)-3- [(trans-4-methylcyclohexyl)methyl]- 6-(5-oxo-4,5- dihydro-1,2,4-oxadiazol-3-yl)-3H- imidazo[4,5-c]pyridin- 2-yl]-N,N,3,5-tetramethylpiperazine- 1-carboxamide TFA 608 608 5.23  1

(3R,5R)-4-[4-(5- chloropyridin-3-yl)-3- [(trans-4-methylcyclohexyl)methyl]- 6-(5-oxo-4,5- dihydro-1,2,4-oxadiazol-3-yl)-3H- imidazo[4,5-c]pyridin- 2-yl]-N-ethyl-N,3,5-trimethylpiperazine-1- carboxamide TFA 622 622 5.24  1

3-{4-(5-chloropyridin- 3-yl)-2-{(2R,6R)-4-[(1- fluorocyclopropyl)carbonyl]-2,6- dimethylpiperazin-1- yl}-3-[(trans-4-methylcyclohexyl)methyl]- 3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one TFA 623 623 5.25  4

3-{4-(5-chloropyridin- 3-yl)-2-{(2R,6R)-4- [(2,2- difluorocyclopropyl)carbonyl]-2,6- dimethylpiperazin-1- yl}-3-[(trans-4- methylcyclohexyl)methyl]-3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one TFA641 641 5.26  4

3-{4-(5-chloropyridin- 3-yl)-2-[(2R,6R)-4- (difluoroacetyl)-2,6-dimethylpiperazin-1- yl]-3-[(trans-4- methylcyclohexyl)methyl]-3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one TFA 615 6155.27 11

3-{4-(5-chloropyridin- 3-yl)-2-{(2R,6R)-2,6- dimethyl-4-[(3-methyloxetan-3- yl)carbonyl]piperazin- 1-yl}-3-[(trans-4-methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one TFA 635 635 5.28 10

3-{4-(5-chloropyridin- 3-yl)-2-{(2R,6R)-2,6- dimethyl-4-[(1-methylcyclopropyl) carbonyl]piperazin-1-yl}- 3-[(trans-4-methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one 619 619 5.29  4

3-{4-(5-chloropyridin- 3-yl)-2-[(2R,6R)-2,6- dimethyl-4-(oxetan-3-ylcarbonyl)piperazin- 1-yl]-3-[(trans-4- methylcyclohexyl)methyl]-3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one TFA 621 6215.30 10

3-{4-(5-chloropyridin- 3-yl)-2-[(2R,6R)-4- (methoxyacetyl)-2,6-dimethylpiperazin-1- yl]-3-[(trans-4- methylcyclohexyl)methyl]-3-imidazo[4,5- c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one 609609

Example 6.1 3-(4-(5-chloropyridin-3-yl)-2-((R orS)-cyclopentyl(ethoxy)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one

Step 1:4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile(product of Step 2, Preparative Example 3.1) (500 mg, 1.367 mmol) wasdissolved in THF (13.7 mL) and cooled to −78° C. in a flask undernitrogen before adding lithium magnesium2,2,6,6-tetramethylpiperidin-1-ide dichloride, 1.0 M in THF (3.01 mL,3.01 mmol). After stirring at −78° C. for 45 minutes,cyclopentanecarbaldehyde (321 μL, 3.01 mmol) was added, and the reactionwas allowed to stir at −78° C. for 30 minutes before removing thecooling bath. After warming to room temperature over 1 hr, the reactionmixture was quenched with sat. aqueous ammonium chloride and extractedwith ethyl acetate. The organic layer was dried over sodium sulfate,filtered, and concentrated. The residue was purified by silica gelchromatography (hexanes/0-65% EtOAc) to afford4-(5-chloropyridin-3-yl)-2-(cyclopentyl(hydroxy)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ESI calc'd. for C₂₆H₃₀ClN₅O [M+H]⁺ 464, found 464. ¹H NMR (600 MHz,CD₃OD) δ 8.78 (d, J=2.1, 1H), 8.74 (d, J=1.3, 1H), 8.27-8.24 (m, 1H),8.23 (s, 1H), 4.68 (d, J=9.1, 1H), 4.15-3.88 (m, 2H), 2.73 (dd, J=8.0,16.0, 1H), 1.99-1.91 (m, 1H), 1.76-1.54 (m, 6H), 1.50 (d, J=13.3, 2H),1.31-1.22 (m, 1H), 1.19-1.09 (m, 1H), 1.02-0.96 (m, 1H), 0.92-0.77 (m,4H), 0.75 (d, J=6.5, 3H), 0.60-0.47 (m, 2H).

Step 2:4-(5-chloropyridin-3-yl)-2-(cyclopentyl(hydroxy)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile(240 mg, 0.517 mmol) was dissolved in THF (5.2 mL) and cooled to 0° C.in a flask under nitrogen before adding sodium hydride (41.4 mg, 1.034mmol). Upon cessation of gas evolution, iodoethane (0.125 μL, 1.552mmol) was added, and the reaction was allowed to warm to roomtemperature overnight. The reaction mixture was quenched with sat.aqueous ammonium chloride and extracted with ethyl acetate. The organiclayer was dried over sodium sulfate, filtered, and concentrated. Theresidue was purified by silica gel chromatography (hexanes/0-40% EtOAc)to afford racemic4-(5-chloropyridin-3-yl)-2-(cyclopentyl(ethoxy)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile.The racemic material was then purified by chiral supercritical fluidchromatography (Chiralpak IC, 21×250 mm, 2-Propanol+0.25% Dimethyl EthylAmine in CO₂) to afford4-(5-chloropyridin-3-yl)-2-(R)-cyclopentyl(ethoxy)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrileand4-(5-chloropyridin-3-yl)-2-((S)-cyclopentyl(ethoxy)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile.¹H NMR (600 MHz, CD₃OD) δ 8.78 (d, J=2.3, 1H), 8.75 (d, J=1.5, 1H), 8.29(t, J=2.0, 1H), 8.24 (s, 1H), 4.65 (d, J=8.5, 1H), 4.08-3.97 (m, 2H),3.59-3.34 (m, 2H), 2.65-2.54 (m, 1H), 1.88-1.77 (m, 1H), 1.73-1.54 (m,6H), 1.49 (d, J=13.2, 2H), 1.30-1.25 (m, 1H), 1.17 (t, J=7.0, 3H),1.15-1.08 (m, 1H), 1.01-0.95 (m, 1H), 0.91-0.76 (m, 4H), 0.75 (d, J=6.6,3H), 0.56-0.45 (m, 2H). MS ESI calc'd. for C₂₈H₃₄ClN₅O [M+H]⁺ 492, found492.

Step 3: Using a procedure analogous to that described in Example 2.1(Step 5), and starting with 4-(5-chloropyridin-3-yl)-2-((R orS)-cyclopentyl(ethoxy)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile,4-(5-chloropyridin-3-yl)-2-((R orS)-cyclopentyl(ethoxy)methyl)-N′-hydroxy-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamidewas prepared.

Step 4: Using a procedure analogous to that described in Example 2.1(Step 6), and starting with 4-(5-chloropyridin-3-yl)-2-((R orS)-cyclopentyl(ethoxy)methyl)-N′-hydroxy-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamide,3-(4-(5-chloropyridin-3-yl)-2-((R orS)-cyclopentyl(ethoxy)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one(enantiomer 1) was prepared. ¹H NMR (600 MHz, CD₃OD) δ 8.80 (d, J=1.7,1H), 8.77 (d, J=2.3, 1H), 8.35-8.34 (m, 2H), 4.68 (d, J=8.3, 1H),4.12-4.01 (m, 2H), 3.62-3.53 (m, 1H), 3.47-3.35 (m, 1H), 2.63-2.54 (m,1H), 1.87-1.77 (m, 1H), 1.76-1.52 (m, 6H), 1.50 (d, J=11.2, 2H),1.36-1.25 (m, 1H), 1.21-1.15 (m, 3H), 1.16-1.08 (m, 1H), 1.05-0.96 (m,1H), 0.95-0.77 (m, 4H), 0.75 (d, J=6.6, 3H), 0.55-0.44 (m, 2H). MS ESIcalc'd. for C₂₉H₃₅ClN₆O₃ [M+H]⁺ 551, found 551.

3-(4-(5-chloropyridin-3-yl)-2-((S orR)-cyclopentyl(ethoxy)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one(enantiomer 2, Example 6.2) was prepared in analogous manner.

Example 6.3 5-(4-(5-chloropyridin-3-yl)-2-((R orS)-cyclopentyl(ethoxy)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,3,4-oxadiazol-2(3H)-one

Using a procedure analogous to that described in Example 2.2 (Step 1 toStep 3), and starting with 4-(5-chloropyridin-3-yl)-2-((R orS)-cyclopentyl(ethoxy)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile,5-(4-(5-chloropyridin-3-yl)-2-((R orS)cyclopentyl(ethoxy)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,3,4-oxadiazol-2(3H)-one(enantiomer 1) was prepared. ¹H NMR (600 MHz, CD₃OD) δ 8.77 (d, J=2.1,2H), 8.30 (t, J=2.1, 1H), 8.26 (s, 1H), 4.69 (d, J=8.2, 1H), 4.03 (d,J=6.8, 2H), 3.64-3.51 (m, 1H), 3.47-3.35 (m, 1H), 2.64-2.47 (m, 1H),1.85-1.76 (m, 1H), 1.75-1.53 (m, 6H), 1.50 (d, J=11.3, 2H), 1.36-1.28(m, 1H), 1.19 (d, J=7.0, 3H), 1.17-1.09 (m, 1H), 1.07-0.97 (m, 1H),0.96-0.77 (m, 4H), 0.75 (d, J=6.6, 3H), 0.58-0.45 (m, 2H). MS ESIcalc'd. for C₂₉H₃₅ClN₆O₃ [M+H]⁺ 551, found551.5-(4-(5-chloropyridin-3-yl)-2-((S orR)cyclopentyl(ethoxy)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,3,4-oxadiazol-2(3H)-one(enantiomer 2, Example 6.4) was prepared in analogous manner.

Example 6.133-(4-(5-chloropyridin-3-yl)-2-(1-ethoxy-2-hydroxyethyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one

Step 1: Using a procedure analogous to that described in Example 6.1(Step 1), and starting with4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Step 2, Preparative Example 3.1) and{[tert-butyl(dimethyl)silyl]oxy}acetaldehyde,2-(2-((tert-butyldimethylsilyl)oxy)-1-hydroxyethyl)-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrilewas prepared.

Step 2: Using a procedure analogous to that described in Example 6.1(Step 2), and starting with2-(2-((tert-butyldimethylsilyl)oxy)-1-hydroxyethyl)-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile,2-(2-((tert-butyldimethylsilyl)oxy)-1-ethoxyethyl)-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrilewas prepared.

Step 3:2-(2-((tert-butyldimethylsilyl)oxy)-1-ethoxyethyl)-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrilewas dissolved in THF (3.9 mL) and cooled to 0° C. before adding TBAF (1M in THF, 1.5 mL). After stirring at 0° C. for 25 minutes, the reactionmixture was diluted with ethyl acetate and washed with water followed bybrine. The organic layer was dried over sodium sulfate, filtered, andconcentrated. The residue was purified by silica gel chromatography(DCM/0-10% MeOH) to afford4-(5-chloropyridin-3-yl)-2-(1-ethoxy-2-hydroxyethyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ESI calc'd. for C₂₄H₂₈ClN₅O₂ [M+H]⁺ 454, found 454.

Step 4: Using a procedure analogous to that described in Example 2.1(Step 5), and starting with4-(5-chloropyridin-3-yl)-2-(1-ethoxy-2-hydroxyethyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile,4-(5-chloropyridin-3-yl)-2-(1-ethoxy-2-hydroxyethyl)-N′-hydroxy-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamidewas prepared.

Step 5: Using a procedure analogous to that described in Example 2.1(Step 6), and starting with4-(5-chloropyridin-3-yl)-2-(1-ethoxy-2-hydroxyethyl)-N′-hydroxy-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamide,3-(4-(5-chloropyridin-3-yl)-2-(1-ethoxy-2-hydroxyethyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-onewas prepared. MS ESI calc'd. for C₂₅H₂₉ClN₆O₄ [M+H]⁺ 513, found 513. ¹HNMR (600 MHz, CD₃OD) δ 8.80 (s, 1H), 8.77 (d, J=2.2, 1H), 8.35 (s, 1H),8.32 (s, 1H), 4.93 (t, J=6.0, 1H), 4.08-3.90 (m, 4H), 3.62 (q, J=7.0,2H), 1.51 (d, J=11.8, 2H), 1.23 (t, J=7.0, 3H), 1.20-1.11 (m, 1H),1.10-0.99 (m, 1H), 0.99-0.91 (m, 1H), 0.90-0.78 (m, 3H), 0.76 (d, J=6.5,3H), 0.60-0.47 (m, 2H).

Example 6.143-(4-(5-chloropyridin-3-yl)-2-(1-ethoxy-2-methoxyethyl)-3-(((1r,4r)-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one

Step 1: Using a procedure analogous to that described in Example 6.1(Step 2), and starting with4-(5-chloropyridin-3-yl)-2-(1-ethoxy-2-hydroxyethyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Example 6.13, Step 3) and iodomethane,4-(5-chloropyridin-3-yl)-2-(1-ethoxy-2-methoxyethyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrilewas prepared. MS ESI calc'd. for C₂₅H₃₀ClN₅O₂ [M+H]⁺ 468, found 468.

Step 2: Using a procedure analogous to that described in Example 2.1(Step 5), and starting with4-(5-chloropyridin-3-yl)-2-(1-ethoxy-2-methoxyethyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile,4-(5-chloropyridin-3-yl)-2-(1-ethoxy-2-methoxyethyl)-N′-hydroxy-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamidewas prepared.

Step 3: Using a procedure analogous to that described in Example 2.1(Step 6), and starting with4-(5-chloropyridin-3-yl)-2-(1-ethoxy-2-methoxyethyl)-N′-hydroxy-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamide,3-(4-(5-chloropyridin-3-yl)-2-(1-ethoxy-2-methoxyethyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-onewas prepared. MS ESI calc'd. for C₂₆H₃₁ClN₆O₄ [M+H]⁺ 527, found 527. ¹HNMR (600 MHz, CD₃OD) δ 8.79 (s, 1H), 8.77 (d, J=2.2, 1H), 8.35 (s, 1H),8.32 (s, 1H), 5.06 (t, J=6.0, 1H), 4.02 (d, J=7.4, 2H), 3.97-3.81 (m,2H), 3.68-3.56 (m, 2H), 3.37 (s, 3H), 1.51 (d, J=11.2, 2H), 1.21 (t,J=7.0, 3H), 1.18-1.11 (m, 1H), 1.09-1.00 (m, 1H), 0.97-0.88 (m, 1H),0.88-0.78 (m, 3H), 0.76 (d, J=6.5, 3H), 0.58-0.47 (m, 2H).

The following compounds in Table 6 (other than Examples 6.1-6.4, 6.13,and 6.14) were prepared using procedures which were analogous to thosedescribed above.

TABLE 6 FRET IC₅₀ [M + H]+ [M + H]+ Ex. (nM) Structure Chemical NameSalt Calc'd Obsv'd 6.1   2

3-{4-(5- chloropyridin-3- yl)-2- [cyclopentyl(ethoxy) methyl]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one (enantiomer 1) TFA 551 551 6.2   3

3-{4-(5- chloropyridin-3- yl)-2- [cyclopentyl(ethoxy) methyl]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one (enantiomer 2) TFA 551 551 6.3   6

5-{4-(5- chloropyridin-3- yl)-2- [cyclopentyl(ethoxy) methyl]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,3,4-oxadiazol- 2(3H)-one (enantiomer 1) TFA 551 551 6.4  10

5-{4-(5- chloropyridin-3- yl)-2- [cyclopentyl(ethoxy) methyl]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,3,4-oxadiazol- 2(3H)-one (enantiomer 2) TFA 551 551 6.5   9

3-(4-(5- chloropyridin-3- yl)-2-(1- ethoxyethyl)-3- ((trans-4-methylcyclohexyl) methyl)-3H- imidazo[4,5- c]pyridin-6-yl)-1,2,4-oxadiazol- 5(4H)-one (enantiomer 1) TFA 497 497 6.6  18

3-(4-(5- chloropyridin-3- yl)-2-(1- ethoxyethyl)-3- ((trans-4-methylcyclohexyl) methyl)-3H- imidazo[4,5- c]pyridin-6-yl)-1,2,4-oxadiazol- 5(4H)-one (enantiomer 2) TFA 497 497 6.7   4

3-(4-(5- chloropyridin-3- yl)-2-(1- ethoxypropyl)-3- ((trans-4-methylcyclohexyl) methyl)-3H- imidazo[4,5- c]pyridin-6-yl)-1,2,4-oxadiazol- 5(4H)-one (enantiomer 1) TFA 511 511 6.8   8

3-(4-(5- chloropyridin-3- yl)-2-(1- ethoxypropyl)-3- ((trans-4-methylcyclohexyl) methyl)-3H- imidazo[4,5- c]pyridin-6-yl)-1,2,4-oxadiazol- 5(4H)-one (enantiomer 2) TFA 511 511 6.9   2

3-(4-(5- chloropyridin-3- yl)-3-((trans-4- methylcyclohexyl)methyl)-2-(1- (2,2,2- trifluoroethoxy) propyl)-3H- imidazo[4,5-c]pyridin-6-yl)- 1,2,4-oxadiazol- 5(4H)-one (racemic) TFA 565 565 6.10 5

3-(4-(5- chloropyridin-3- yl)-3-((trans-4- methylcyclohexyl)methyl)-2-(1- (2,2,2- trifluoroethoxy) propyl)-3H- imidazo[4,5-c]pyridin-6-yl)- 1,2,4-oxadiazol- 5(4H)-one (enantiomer 1) 565 565 6.11 2

3-(4-(5- chloropyridin-3- yl)-3-((trans-4- methylcyclohexyl)methyl)-2-(1- (2,2,2- trifluoroethoxy) propyl)-3H- imidazo[4,5-c]pyridin-6-yl)- 1,2,4-oxadiazol- 5(4H)-one (enantiomer 2) 565 565 6.12 3

3-(4-(5- chloropyridin-3- yl)-3-((trans-4- methylcyclohexyl)methyl)-2-(1- propoxypropyl)- 3H-imidazo[4,5- c]pyridin-6-yl)-1,2,4-oxadiazol- 5(4H)-one (racemic) TFA 525 525 6.13 15

3-{4-(5- chloropyridin-3- yl)-2-(1-ethoxy-2- hydroxyethyl)-3- [(trans-4-methylcyclohexyl) methyl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one (racemic) TFA 513 513 6.14  9

3-{4-(5- chloropyridin-3- yl)-2-(1-ethoxy-2- methoxyethyl)-3- [(trans-4-methylcyclohexyl) methyl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one (racemic) TFA 527 527 6.15  2

3-{4-(5- chloropyridin-3- yl)-2- [cyclopropyl(ethoxy) methyl]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one (racemic) TFA 523 523 6.16  1

3-{4-(5- chloropyridin-3- yl)-2- [cyclopropyl(ethoxy) methyl]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one (enantiomer 1) 523 523 6.17  4

3-{4-(5- chloropyridin-3- yl)-2- [cyclopropyl(ethoxy) methyl]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one (enantiomer 2) 523 523 6.18  2

3-{4-(5- chloropyridin-3- yl)-2- [ethoxy(tetrahydro- 2H-pyran-4-yl)methyl]-3- [(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (racemic) TFA 567 567 6.19 5

3-{4-(5- chloropyridin-3- yl)-2- [ethoxy(tetrahydro- 2H-pyran-4-yl)methyl]-3- [(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (enantiomer 1) 567 567 6.20 3

3-{4-(5- chloropyridin-3- yl)-2- [ethoxy(tetrahydro- 2H-pyran-4-yl)methyl]-3- [(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (enantiomer 2) 567 567 6.21 2

3-{4-(5- chloropyridin-3- yl)-2- [cyclopropyl(2- methoxyethoxy)methyl]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (racemic) TFA 553 553 6.22 2

3-{4-(5- chloropyridin-3- yl)-2- [cyclopropyl(2- methoxyethoxy)methyl]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (enantiomer 1) 553 553 6.23 7

3-{4-(5- chloropyridin-3- yl)-2- [cyclopropyl(2- methoxyethoxy)methyl]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (enantiomer 2) 553 553

Example 7.1 3-{4-(5-chloropyridin-3-yl)-2-[(R orSyethoxy(phenyl)methyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one

Step 1:4-(5-chloropyridin-3-yl)-2-(hydroxy(phenyl)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrilewas prepared using4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile(product of Step 2, Preparative Example 3.1) and benzaldehyde in amanner analogous to Example 6.1, Step 1. ¹H NMR (600 MHz, CD₃OD) δ 8.75(d, J=2.2, 1H), 8.69 (s, 1H), 8.26 (s, 1H), 8.21 (s, 1H), 7.48 (d,J=7.5, 2H), 7.37 (t, J=7.5, 2H), 7.34-7.28 (m, 1H), 6.22 (s, 1H), 3.94(s, 2H), 1.40 (t, J=14.0, 2H), 1.06-0.98 (m, 1H), 0.83-0.77 (m, 1H),0.75-0.68 (m, 5H), 0.64-0.56 (m, 1H), 0.51-0.36 (m, 3H). MS ESI calc'd.for C₂₇H₂₆ClN₅O [M+H]⁺ 472, found 472.

Step 2: To a solution of4-(5-chloropyridin-3-yl)-2-(hydroxy(phenyl)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile(276 mg, 0.585 mmol) in NMP (3 mL) was added lithium hydroxide (28.0 mg,1.170 mmol) and iodoethane (142 μL, 1.754 mmol), and the reactionmixture was allowed to stir at room temperature overnight. The reactionmixture was quenched with sat. aqueous ammonium chloride and extractedwith ethyl acetate. The organic layer was dried over sodium sulfate,filtered, and concentrated. The residue was purified by silica gelchromatography (hexanes/0-50% EtOAc) to afford racemic4-(5-chloropyridin-3-yl)-2-(ethoxy(phenyl)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile.The racemic material was then purified by chiral supercritical fluidchromatography (Chiralpak OJ-H, 21×250 mm, MeOH in CO₂) to afford4-(5-chloropyridin-3-yl)-2-(R)-ethoxy(phenyl)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrileand4-(5-chloropyridin-3-yl)-2-(S)-ethoxy(phenyl)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ESI calc'd. for C₂₉H₃₀ClN₅O [M+H]⁺ 500, found 500. ¹H NMR (600 MHz,CD₃OD) δ 8.75 (d, J=2.3, 1H), 8.70 (d, J=1.6, 1H), 8.27 (s, 1H), 8.23(t, J=2.0, 1H), 7.49 (d, J=7.2, 2H), 7.38 (t, J=7.3, 2H), 7.36-7.31 (m,1H), 5.94 (s, 1H), 4.01-3.85 (m, 2H), 3.68-3.59 (m, 2H), 1.44-1.36 (m,2H), 1.27 (t, J=7.0, 3H), 1.07-0.98 (m, 1H), 0.89-0.78 (m, 1H),0.76-0.66 (m, 5H), 0.64-0.54 (m, 1H), 0.54-0.46 (m, 1H), 0.46-0.36 (m,2H).

Step 3: Using a procedure analogous to that described in Example 2.1(Step 5 and Step 6), and starting with 4-(5-chloropyridin-3-yl)-2-((R orS)-ethoxy(phenyl)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile,3-{4-(5-chloropyridin-3-yl)-2-[(R orS)-ethoxy(phenyl)methyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(enantiomer 1) was prepared. MS ESI calc'd. for C₃₀H₃₁ClN₆O₃ [M+H]⁺ 559,found 559. ¹H NMR (600 MHz, CD₃OD) δ 8.74 (t, J=2.1, 2H), 8.36 (s, 1H),8.29 (t, J=2.0, 1H), 7.50 (d, J=7.3, 2H), 7.42-7.37 (m, 2H), 7.37-7.33(m, 1H), 5.96 (s, 1H), 4.04-3.88 (m, 2H), 3.70-3.61 (m, 2H), 1.44-1.36(m, 2H), 1.29 (t, J=7.0, 3H), 1.07-0.98 (m, 1H), 0.88-0.79 (m, 1H),0.78-0.65 (m, 5H), 0.63-0.53 (m, 1H), 0.53-0.44 (m, 1H), 0.44-0.34 (m,2H).

3-{4-(5-chloropyridin-3-yl)-2-[(S orR)-ethoxy(phenyl)methyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(Example 7.2, enantiomer 2) was prepared in an analogous manner.

The following compounds in Table 7 (other than Example 7.1 and 7.2) wereprepared using procedures which were analogous to those described above.

TABLE 7 FRET IC₅₀ [M + H]+ [M + H]+ Ex. (nM) Structure Chemical NameSalt Calc'd Obsv'd 7.1 1

3-{4-(5-chloropyridin-3- yl)-2- [ethoxy(phenyl)methyl]- 3-[(trans-4-methylcyclohexyl)methyl]- 3H-imidazol[4,5-c] pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (enantiomer 1) TFA 559 559 7.2 4

3-{4-(5-chloropyridin-3- yl)-2- [ethoxy(phenyl)methyl]- 3-[(trans-4-methylcyclohexyl)methyl]- 3H-imidazol[4,5-c] pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (enantiomer 2) TFA 559 559 7.3 19 

3-{4-(5-chloropyridin-3- yl)-2-[(2,4- difluorophenyl)(hydroxy)methyl]-3-[(trans-4- methylcyclohexyl)methyl]- 3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one TFA 567 567 7.4 2

3-{4-(5-chloropyridin-3- yl)-2-[(2- fluorophenyl)(hydroxy)methyl]-3-[(trans-4- methylcyclohexyl)methyl]- 3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one TFA 549 549 7.5 5

3-{4-(5-chloropyridin-3- yl)-2-(1-hydroxy-2- methoxy-1-phenylethyl)-3-[(trans-4- methylcyclohexyl)methyl]- 3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one (racemic) TFA 575 575 7.6 2

3-(4-(5-chloropyridin-3- yl)-2-(ethoxy(pyridin-2-yl)methyl)-3-((trans-4- methylcyclohexyl)methyl)- 3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4- oxadiazol-5(4H)-one (racemic) TFA 560 560 7.7 5

3-(4-(5-chloropyridin-3- yl)-2-(ethoxy(pyridin-3-yl)methyl)-3-((trans-4- methylcyclohexyl)methyl)- 3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4- oxadiazol-5(4H)-one (racemic) TFA 560 560 7.8 6

3-(4-(5-chloropyridin-3- yl)-2-(ethoxy(pyridin-2-yl)methyl)-3-((trans-4- methylcyclohexyl)methyl)- 3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4- oxadiazol-5(4H)-one (enantiomer 1) 560 560 7.9 2

3-(4-(5-chloropyridin-3- yl)-2-(ethoxy(pyridin-2-yl)methyl)-3-((trans-4- methylcyclohexyl)methyl)- 3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4- oxadiazol-5(4H)-one (enantiomer 2) 560 560 7.10 2

3-{4-(5-chloropyridin-3- yl)-2-[ethoxy(1,3- thiazol-4-yl)methyl]-3-[(trans-4- methylcyclohexyl)methyl]- 3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one (racemic) TFA 566 566 7.11 3

3-{4-(5-chloropyridin-3- yl)-2-[ethoxy(1-methyl-1H-pyrazol-3-yl)methyl]- 3-[(trans-4- methylcyclohexyl)methyl]-3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one (racemic) TFA563 563 7.12 3

3-{4-(5-chloropyridin-3- yl)-2-[ethoxy(1,3- thiazol-4-yl)methyl]-3-[(trans-4- methylcyclohexyl)methyl]- 3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one (enantiomer 1) 566 566 7.13 7

3-{4-(5-chloropyridin-3- yl)-2-[ethoxy(1,3- thiazol-4-yl)methyl]-3-[(trans-4- methylcyclohexyl)methyl]- 3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one (enantiomer 2) 566 566 7.14 3

3-{4-(5-chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-[pyridin-2-yl(2,2,2- trifluoroethoxy)methyl]- 3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one (racemic) TFA 614 614

Example 8.13-{4-(5-chloropyridin-3-yl)-2-[(2-fluorophenyl)carbonyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one

To a room temperature slurry of3-{4-(5-chloropyridin-3-yl)-2-[(2-fluorophenyl)(hydroxy)methyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(Example 7.4 in Table 7, 150 mg, 0.273 mmol) in dichloromethane (4 mL)was added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (127mg, 0.301 mmol). The mixture was stirred at room temperature for 1 hourduring which time it became a homogeneous solution. Saturated aqueoussodium thiosulfate was added, and the resulting mixture was extractedwith ethyl acetate (2×). The combined organic layers were dried oversodium sulfate, filtered, and concentrated. Purification via mass guidedreverse phase HPLC (acetonitrile/water+0.1% TFA modifier) afforded3-{4-[5-chloropyridin-3-yl)-2-(2-fluorophenyl)carbonyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(TFA salt) as a white solid. MS ESI calcd. for C₂₈H₂₄ClFN₆O₃ [M+H]⁺ 547,found 547. ¹H NMR (500 MHz, DMSO-d₆) δ 13.01 (s, 1H), 8.96 (s, 1H), 8.89(s, 1H), 8.51 (s, 1H), 8.45 (s, 1H), 7.85-7.87 (m, 2H), 7.45-7.41 (m,2H), 4.25 (d, J=6.5 Hz, 2H), 1.43-1.40 (m, 2H), 1.15-1.02 (m, 2H),0.86-0.80 (m, 2H), 0.73-0.65 (m, 5H), 0.55-0.50 (m, 2H).

Example 8.23-{4-(5-chloropyridin-3-yl)-2-[1-fluoro-1-(2-fluorophenyl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one

Step 1: To a solution of3-{4-(5-chloropyridin-3-yl)-2-[(2-fluorophenyl)carbonyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(Example 8.1, 44 mg, 0.08 mmol) in tetrahydrofuran (0.8 mL) at −78° C.was added dropwise methyl magnesium bromide (0.054 mL of 3.0 M indiethyl ether, 0.161 mmol). The reaction was stirred and slowly warmedto −20° C. over 3 hours. The reaction was then quenched via the additionof saturated aqueous ammonium chloride and extracted with ethyl acetate(2×). The combined organics were dried over magnesium sulfate, filtered,and concentrated under reduced pressure. The resulting residue waspurified via silica gel chromatography (0-10% methanol/DCM) to afford3-{4-(5-chloropyridin-3-yl)-2-[1-(2-fluorophenyl)-1-hydroxyethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-oneas a white solid. MS ESI calcd. for C₂₉H₂₈ClFN₆O₃ [M+H]⁺ 563, found 563.

Step 2: To a room temperature slurry of3-{4-(5-chloropyridin-3-yl)-2-[1-(2-fluorophenyl)-1-hydroxyethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(38 mg, 0.067 mmol) in dichloromethane (1.35 mL) was addedN,N-diethylaminosulfur trifluoride (0.045 mL, 0.337 mmol). The mixturewas stirred for one hour, then quenched with saturated aqueous sodiumbicarbonate and extracted with dichloromethane (2×). The combinedorganic layers were washed with brine (1×), dried over magnesiumsulfate, filtered, and concentrated under reduced pressure. Theresulting residue was purified via silica gel chromatography (0-100%ethyl acetate/hexanes) to afford3-{4-(5-chloropyridin-3-yl)-2-[1-fluoro-1-(2-fluorophenyl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-oneas a white solid. MS ESI calcd. for C₂₉H₂₇ClF₂N₆O₂ [M+H]⁺ 565, found565. ¹H NMR (500 MHz, DMSO-d₆) δ 12.97 (s, 1H), 8.86 (s, 1H), 8.82 (s,1H), 8.45 (s, 1H), 8.38 (s, 1H), 7.68-7.57 (m, 1H), 7.52-7.50 (m, 1H),7.35-7.32 (m, 1H), 7.26-7.22 (m, 1H), 3.84-3.78 (m, 1H), 2.28 (d, J=23Hz, 3H), 1.35-1.33 (m, 1H), 1.28-1.18 (m, 2H), 0.93-0.80 (m, 2H),0.72-0.62 (m, 5H), 0.54-0.43 (m, 2H), 0.33-0.23 (m, 2H).

Examples 8.3 and 8.4 3-{4-(5-chloropyridin-3-yl)-2-[(1R orS)-1-fluoro-1-(2-fluorophenyl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-oneand 3-{4-(5-chloropyridin-3-yl)-2-[(1S orR)-1-fluoro-1-(2-fluorophenyl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one

The enantiomers of3-{4-(5-chloropyridin-3-yl)-2-[(2-fluorophenyl)carbonyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(Example 8.2) were separated by chiral SFC chromatography (ChiralpakAS-H, 21×250 mm, 25% methanol in CO₂+0.25% dimethylethylamine modifier,flow rate=70 mL/min) to afford 3-{4-(5-chloropyridin-3-yl)-2-[(1R orS)-1-fluoro-1-(2-fluorophenyl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-oneand 3-{4-(5-chloropyridin-3-yl)-2-[(1S orR)-1-fluoro-1-(2-fluorophenyl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-oneboth as white solids.

3-{4-(5-chloropyridin-3-yl)-2-[(1R orS)-1-fluoro-1-(2-fluorophenyl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(enantiomer 1, Example 8.3): T_(R)=2.58 min. MS ESI calcd. forC₂₉H₂₇ClF₂N₆O₂ [M+H]⁺ 565, found 565. ¹H NMR (500 MHz, DMSO-d₆) δ 12.97(s, 1H), 8.86 (s, 1H), 8.82 (s, 1H), 8.45 (s, 1H), 8.38 (s, 1H),7.68-7.57 (m, 1H), 7.52-7.50 (m, 1H), 7.35-7.32 (m, 1H), 7.26-7.22 (m,1H), 3.84-3.78 (m, 1H), 2.28 (d, J=23 Hz, 3H), 1.35-1.33 (m, 1H),1.28-1.18 (m, 2H), 0.93-0.80 (m, 2H), 0.72-0.62 (m, 5H), 0.54-0.43 (m,2H), 0.33-0.23 (m, 2H).

3-{4-(5-chloropyridin-3-yl)-2-[(1S orR)-1-fluoro-1-(2-fluorophenyl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(enantiomer 2, Example 8.4): T_(R)=5.48 min. MS ESI calcd. forC₂₉H₂₇ClF₂N₆O₂ [M+H]⁺ 565, found 565. ¹H NMR (500 MHz, DMSO-d₆) δ 12.97(s, 1H), 8.86 (s, 1H), 8.82 (s, 1H), 8.45 (s, 1H), 8.38 (s, 1H),7.68-7.57 (m, 1H), 7.52-7.50 (m, 1H), 7.35-7.32 (m, 1H), 7.26-7.22 (m,1H), 3.84-3.78 (m, 1H), 2.28 (d, J=23 Hz, 3H), 1.35-1.33 (m, 1H),1.28-1.18 (m, 2H), 0.93-0.80 (m, 2H), 0.72-0.62 (m, 5H), 0.54-0.43 (m,2H), 0.33-0.23 (m, 2H).

Examples 8.6 and 8.7 3-{4-(5-chloropyridin-3-yl)-2-[(1R orS)-1-fluoro-1-(3-fluoropyridin-2-yl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-oneand 3-{4-(5-chloropyridin-3-yl)-2-[(1S orR)-1-fluoro-1-(3-fluoropyridin-2-yl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one

Step 1: To a stirred solution of6-chloro-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine(Preparative Example 3.1, Step 1) (1.2 g, 3.19 mmol) in THF (20 mL) wasadded 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloridecomplex (Aldrich, 1M in THF/toluene) (5.11 mL, 5.11 mmol) at −78° C.,and the reaction was stirred at −78° C. for 2 hours under a nitrogenatmosphere. 3-fluoropicolinaldehyde (1.1 g, 9.59 mmol) dissolved in THF(4.0 mL) was added dropwise at −78° C., and the reaction was stirred foran additional 2 hours at −78° C. The reaction was quenched with aqueoussaturated NH₄Cl solution (50 mL) and extracted with ethyl acetate (2×40mL). The combined organic extracts were washed with brine (20 mL), driedover anhydrous Na₂SO₄, filtered, and concentrated. Purification of theresidue on a silica gel column (0 to 100% EtOAc/hexanes) afforded{6-chloro-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-2-yl}(3-fluoropyridin-2-yl)methanol.MS APCl calcd. for C₂₅H₂₄Cl₂FN₅O [M+H]⁺ 500, found 500.

Step 2: To a stirred solution of{6-chloro-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-2-yl}(3-fluoropyridin-2-yl)methanol(807 mg, 1.61 mmol) in dichloromethane (15 mL) was added Dess-Martinperiodinane (2.7 g, 6.45 mmol.) at 0° C. Then reaction was graduallywarmed to room temperature and stirred for 2 hours. The reaction mixturewas diluted with dichloromethane (15 mL), quenched with aqueoussaturated NaHCO₃ solution (40 mL), and extracted with dichloromethane(2×30 mL). The combined organic extracts were washed with brine (10 mL),dried over anhydrous Na₂SO₄, filtered, and concentrated. Purification ofthe residue on a silica gel column (0 to 100% EtOAc/hexanes) afforded{6-chloro-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-2-yl}(3-fluoropyridin-2-yl)methanone.MS APCl calcd. for C₂₅H₂₂Cl₂FN₅O [M+H]⁺ 498, found 498.

Step 3: To a stirred solution of{6-chloro-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-2-yl}(3-fluoropyridin-2-yl)methanone(618 mg, 1.24 mmol) in THF (10 mL) was added methyl magnesium bromide (3M in diethyl ether, 0.82 mL, 2.46 mmol) at −78° C., and the reactionmixture was stirred for 2 hours. The reaction mixture was quenched withaqueous saturated NH₄Cl solution (40 mL) and extracted with ethylacetate (2×35 mL). The combined organic extracts were washed with brine(20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated.Purification of the residue on a silica gel column (0 to 100%EtOAc/hexanes) afforded(1RS)-1-{6-chloro-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-2-yl}-1-(3-fluoropyridin-2-yl)ethanol.MS APCl calcd. for C₂₆H₂₆Cl₂FN₅O [M+H]⁺ 514, found 514.

Step 4: An oven-dried reaction vial was charged with(1RS)-1-{6-chloro-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-2-yl}-1-(3-fluoropyridin-2-yl)ethanol(440 mg, 0.85 mmol, 1.0 equiv), Zn(CN)₂ (45 mg, 0.38 mmol, 0.45 equiv),Pd(PPh₃)₄ (246 mg, 0.21 mmol, 0.25 equiv) and degassed DMA (3.5 mL). Thereaction mixture was degassed again and sealed. The reaction was heatedat 100° C. for 6 hours. The reaction was then cooled to room temperatureand diluted with water (15 mL). The mixture was extracted with ethylacetate (3×20 mL). The organic layers were combined, washed with brine(2×10 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was loaded onto a C-18column and purified using 0-100% acetonitrile/water to afford4-(5-chloropyridin-3-yl)-2-[(1RS)-1-(3-fluoropyridin-2-yl)-1-hydroxyethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS APCl calcd. for C₂₇H₂₆ClFN₆O [M+H]⁺505, found 505.

Step 5: To a solution of4-(5-chloropyridin-3-yl)-2-[(1RS)-1-(3-fluoropyridin-2-yl)-1-hydroxyethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(156 mg, 0.31 mmol) in CH₂Cl₂ (10.0 mL) at −40° C. under a nitrogenatmosphere was added DAST (0.08 mL, 0.22 mmol), and the resultingsolution was stirred at this temperature for 1 hour. The reactionmixture was then quenched with a saturated aqueous solution of NaHCO₃ (5mL) and extracted with CH₂Cl₂ (2×15 mL). The combined organic layerswere washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered,and concentrated. Purification of the resulting residue on a silica gelcolumn (0 to 100% ethyl acetate/hexanes) afforded4-(5-chloropyridin-3-yl)-2-[(1RS)-1-fluoro-1-(3-fluoropyridin-2-yl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS APCl calcd. for C₂₇H₂₅ClF₂N₆ [M+H]⁺ 507, found 507. The twoenantiomers were separated on a chiralpak-AD column (15% IPA/heptane) toafford faster eluting Enantiomer A and slower eluting Enantiomer B.

Steps 6 & 7: Using conditions similar to those described in Example 2.1,(Steps 5 and 6) 4-(5-chloropyridin-3-yl)-2-[(1R orS)-1-fluoro-1-(3-fluoropyridin-2-yl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Enantiomer A) and 4-(5-chloropyridin-3-yl)-2-[(1 S orR)-1-fluoro-1-(3-fluoropyridin-2-yl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Enantiomer B) were converted to 3-{4-(5-chloropyridin-3-yl)-2-[(1R orS)-1-fluoro-1-(3-fluoropyridin-2-yl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-oneand 3-{4-(5-chloropyridin-3-yl)-2-[(1S orR)-1-fluoro-1-(3-fluoropyridin-2-yl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one.MS ES calcd. for C₂₈H₂₆ClF₂N₇O₂ [M+H]⁺ 566, found 566. ¹H NMR (400 MHz,CD₃OD) δ 8.77 (br s, 1H), 8.75 (d, J=2.4 Hz, 1H), 8.40 (d, J=4.4 Hz,1H), 8.36 (s, 1H), 8.33 (m, 1H), 7.70 (m, 1H), 7.57 (m, 1H), 3.88-3.94(m, 2H), 2.37 (d, J=21.6 Hz, 3H), 1.42-1.48 (m, 2H), 1.08 (m, 1H),0.82-0.95 (m, 2H), 0.74 (d, J=6.8 Hz, 3H), 0.40-0.68 (m, 5H).

Example 8.143-{4-(5-chloropyridin-3-yl)-2-(1-fluoro-2-methoxy-1-methylethyl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(racemate)

Step 1:4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Preparative Example 3.1, Step 2) (350 mg, 0.95 mmol) was dissolved inTHF (10 mL) and cooled to −78° C.2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloridecomplex (Aldrich, 1M in THF/toluene) (2.0 mL, 2.0 mmol) was added slowlyto the solution at −78° C. The reaction was stirred at −78° C. for 2hours. Then methoxyacetone (168 mg, 2.0 mmol) was added into thereaction mixture at −78° C. The reaction was allowed to warm to roomtemperature and stirred for 8 hours under a nitrogen atmosphere. Thereaction was quenched with saturated NH₄Cl solution (5 mL) at −78° C.and extracted with EtOAc (2×10 mL). The combined organic layers weredried over anhydrous Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified on a silica gel column (0 to 100%EtOAc/hexanes) to afford4-(5-chloropyridin-3-yl)-2-(2-hydroxy-1-methoxypropan-2-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS APCl calcd. for C₂₄H₂₈ClN₅O₂ [M+H]⁺ 454, found 454.

Steps 2, 3, & 4: Using procedures similar to those described in Example8.6/8.7 (Step 5) and Example 2.1, (Steps 5 and 6),4-(5-chloropyridin-3-yl)-2-(2-hydroxy-1-methoxypropan-2-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrilewas converted to3-{4-(5-chloropyridin-3-yl)-2-(1-fluoro-2-methoxy-1-methylethyl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(racemate). ¹H NMR (400 MHz, CD₃OD) δ 8.74 (d, J=2.0 Hz, 1H), 8.51 (s,1H), 8.47 (s, 1H), 8.22 (d, J=2.0 Hz, 1H), 4.14-4.22 (m, 1H), 3.92-3.97(m, 3H), 3.42 (s, 3H), 1.85 (d, J=22 Hz, 3H), 1.52 (m, 2H), 1.20 (m,3H), 0.95-0.98 (m, 3H), 0.78 (d, J=6.8 Hz, 3H) 0.54-0.64 (m, 2H). MSAPCl calcd. for C₂₅H₂₈ClFN₆O₃ [M+H]⁺ 515, found 515.

Example 8.153-{4-(5-chloropyridin-3-yl)-2-[1-(3-fluoropyridin-2-yl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(racemate)

Step 1: To a stirred solution of(1RS)-1-{6-chloro-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-2-yl}-1-(3-fluoropyridin-2-yl)ethanol(Example 8.6/8.7, Step 3; 1.2 g, 2.33 mmol) and pyridine (1.88 mL, 23.3mmol) in dichloromethane (20 mL) was added thionyl chloride (0.85 mL,11.67 mmol) dropwise at 0° C., and the reaction was stirred at 0° C. for1 h. The reaction was quenched with saturated NaHCO₃ solution andextracted with dichloromethane (2×25 mL). The combined organic extractswere washed with water (1×25 mL) and brine (1×25 mL), dried overanhydrous Na₂SO₄, filtered, and concentrated. The residue was purifiedon a silica gel column (eluting with 40-60% EtOAc/petroleum ether) toafford6-chloro-4-(5-chloropyridin-3-yl)-2-[1-(3-fluoropyridin-2-yl)ethenyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine.MS ES/APCl calcd. for C₂₆H₂₄C₁₂FN₅ [M+H]⁺ 496, found 496.

Step 2: To a stirred solution of6-chloro-4-(5-chloropyridin-3-yl)-2-[1-(3-fluoropyridin-2-yl)ethenyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine(530 mg, 1.07 mmol) in EtOAc (12 mL) was added platinum(IV) oxide (53mg). The reaction was placed under a H₂ atmosphere and stirred for 3 h.The reaction was filtered through celite, washing with MeOH, and thefiltrate was concentrated. The residue was purified by silica gelchormatography (eluting with 38-50% EtOAc/petroleum ether) to yield6-chloro-4-(5-chloropyridin-3-yl)-2-[1-(3-fluoropyridin-2-yl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine.MS ES/APCl calcd. for C₂₆H₂₆C₁₂FN₅ [M+H]⁺ 498, found 498.

Step 3: To a stirred solution of6-chloro-4-(5-chloropyridin-3-yl)-2-[1-(3-fluoropyridin-2-yl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine(400 mg, 0.80 mmol) in DMF (16 mL) was added zinc cyanide (37.7 mg, 0.32mmol), and the reaction was deoxygenated by purging with nitrogen for 10minutes. 1,1-Bis(diphenylphosphino)ferrocene-palladium(II)ichloridedichloromethane complex (65.5 mg, 0.08 mmol) was added, and the reactionmixture was again deoxygenated for 5 minutes. The reaction was heated to140° C. for 5 h under a nitrogen atmosphere. The reaction was thencooled to room temperature, diluted with water (25 mL), and extractedwith ethyl acetate (2×25 mL). The combined organic extracts were washedwith water (1×25 mL) and brine (1×25 mL), dried over anhydrous Na₂SO₄,filtered, and concentrated. The residue was purified by silica gelchormatography (eluting with 35% EtOAc/petroleum ether) to yield4-(5-chloropyridin-3-yl)-2-[1-(3-fluoropyridin-2-yl)ethyl]-3-[(trans-4-methylcyclohexypmethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ES/APCl calcd. for C₂₇H₂₆ClFN₆ [M+H]⁺ 489, found 489.

Steps 4 & 5: Using procedures similar to those described in Example 2.1,(Steps 5 and 6)4-[5-chloropyridin-3-yl)-2-[1-(3-fluoropyridin-2-yl)ethyl]-3-[(trans-4-methylcyclohexypmethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrilewas converted to3-{4-(5-chloropyridin-3-yl)-2-[1-(3-fluoropyridin-2-yl)ethyl]-3-[(trans-4-methylcyclohexypmethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(racemate). MS ES/APCl calcd. for C₂₈H₂₇ClFNγO₂ [M+H]⁺ 548, found 548.¹H NMR (400 MHz, DMSO-d₆): δ 12.50 (bs, 1H), 8.83 (d, J=2.00 Hz, 1H),8.80 (s, 1H), 8.42-8.38 (m, 2H), 8.14 (s, 1H), 7.75-7.70 (m, 1H),7.47-7.43 (m, 1H), 4.97-4.95 (m, 1H), 3.81-3.57 (m, 2H), 1.78-1.74 (m,3H), 1.45-1.35 (m, 2H), 1.29-1.04 (m, 3H), 0.89-0.84 (m, 2H), 0.76-0.70(m, 3H), 0.56-0.43 (m, 3H).

Examples in Table 8 (other than Examples 8.1-8.4, 8.6-8.7 and 8.14-8.15)were prepared using procedures that were analogous to those describedabove.

TABLE 8 FRET IC₅₀ [M + H]+ [M + H]+ Ex. (nM) Structure Chemical NameSalt Calc'd Obsv'd 8.1  2

3-{4-(5- chloropyridin-3-yl)- 2-[(2- fluorophenyl)carbonyl]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c] pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one TFA 547 547 8.2  2

3-{4-(5- chloropyridin-3-yl)- 2-[1-fluoro-1-(2- fluorophenyl)ethyl]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c] pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one (racemic) TFA 565 565 8.3  1

3-{4-(5- chloropyridin-3-yl)- 2-[(1R or S)-1- fluoro-1-(2-fluorophenyl)ethyl]- 3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5-c] pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (enantiomer 1)TFA 565 565 8.4 20

3-{4-(5- chloropyridin-3-yl)- 2-[(1S or R)-1- fluoro-1-(2-fluorophenyl)ethyl]- 3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (enantiomer 2)TFA 565 565 8.5  2

3-{4-(5- chloropyridin-2- 2-[1-(2,4- difluorophenyl)-1- fluoroethyl]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one (racemic) TFA 583 583 8.6  9

3-{4-(5- chloropyridin-3-yl)- 2-[(1R or S)-1- fluoro-1-(3-fluoropyridin-2- yl)ethyl]-3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (enantiomer 1)566 566 8.7 <1

3-{4-(5- chloropyridin-3-yl)- 2-[(1S or R)-1- fluoro-1-(3-fluoropyridin-2- yl)ethyl]-3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (Enantiomer 2)566 566 8.8  4

3-{4-(5- chloropyridin-3-yl)- 2-[(1R or S)-1- fluoro-1-(3-fluoropyridin-4- yl)ethyl]-3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (Enantiomer 1)566 566 8.9  1

3-{4-(5- chloropyridin-3-yl)- 2-[(1S or R)-1- fluoro-1-(3-fluoropyridin-4- yl)ethyl]-3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (Enantiomer 2)566 566 8.10 11

3-{4-(5- chloropyridin-3-yl)- 2-[(1R or S)-1- fluoro-1-(3-methylpyridin-2- yl)ethyl]-3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (Enantiomer 1)562 562 8.11 <1

3-{4-(5- chloropyridin-3-yl)- 2-[(1S or R)-1- fluoro-1-(3-methylpyridin-2- yl)ethyl]-3-[(trans-4- methylcyclohexyl) methyl]-3H-imidazo[4,5- c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (Enantiomer 2)562 562 8.12  3

3-{4-(5- chloropyridin-3-yl)- 2-[(1R or S)-1- fluoro-1-(pyridin-2-yl)ethyl]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (Enantiomer 1) 548 548 8.13 2

3-{4-(5- chloropyridin-3-yl)- 2-[(1S or R)-1- fluoro-1-(pyridin-2-yl)ethyl]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (Enantiomer 2) 548 548 8.1421

3-{4-(5- chloropyridin-3-yl)- 2-(1-fluoro-2- methoxy-1- methylethyl)-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one (racemate) 515 515 8.15  4

3-{4-(5- chloropyridin-3-yl)- 2-[1-(3- fluoropyridin-2-yl)ethyl]-3-[(trans-4- methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one (racemate) 548 548

Preparative Example 9.14,4,5,5-tetramethyl-2-(3-methylbut-1-en-2-yl)-1,3,2-dioxaborolane

Step 1: A solution of 3-methylbut-1-yne (2 g, 29.3 mmol) in anhydrousn-pentane (5.0 mL) was cooled to −30° C. (dry ice/acetonitrile).Trifluoromethanesulfonic acid (2.2 g, 14.6 mmol) was slowly addeddropwise, and the reaction was stirred at −30° C. for 2 h. The reactionmixture was quenched with saturated sodium bicarbonate (5 mL) andextracted with diethyl ether (2×5 mL). The combined organic layers werewashed with sodium bicarbonate solution (10 mL) and brine (10 mL), driedover anhydrous Na₂SO₄, filtered, and concentrated under reducedpressure. The crude 3-methylbut-1-en-2-yl trifluoromethanesulfonate wastaken into next step without further purification.

Step 2: To a stirred solution of 3-methylbut-1-en-2-yltrifluoromethanesulfonate (2.0 g, 29.3 mmol) in toluene (40 mL), sodiumphenoxide (3.74 g, 32.23 mmol) and bis(pinacolato)diboron (8.18 g, 32.23mmol) were added, and the mixture was degassed with argon for 10minutes. Triphenylphospine (0.46 g, 1.758 mmol) and PdCl₂(PPh₃)₂ (1.02g, 1.45 mmol) were added, and the reaction was heated to 60° C. for 12h. The reaction mixture was quenched with ice and extracted with ethylacetate (3×50 mL). The combined organic layers were washed with sodiumbicarbonate solution (25 mL) and brine (25 mL), dried over anhydrousNa₂SO₄, filtered, and concentrated. The residue was purified by silicagel column chromatography using 15% ethyl acetate/petroleum ether aseluent to give4,4,5,5-tetramethyl-2-(3-methylbut-1-en-2-yl)-1,3,2-dioxaborolane. ¹HNMR (400 MHz, CDCl₃): δ 5.72 (d, J=3.0 Hz, 1H), 5.60 (d, J=3.0 Hz, 1H),2.47-2.50 (m, 1H), 1.25-1.36 (m, 12H), 1.06 (d, J=6.8 Hz, 6H).

Example 9.13-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(1-phenylethenyl)-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one

Step 1: A sealed tube was charged with2-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Preparative Example 3.1, 150 mg, 0.337 mmol),4,4,5,5-tetramethyl-2-(1-phenylethenyl)-1,3,2-dioxaborolane (93 mg,0.405 mmol), PdCl₂(dppf)-dichloromethane adduct (27.5 mg, 0.034 mmol),and potassium phosphate (215 mg, 1.012 mmol). The tube was evacuated andbackfilled with argon (3×). Fully degassed dioxane (1.53 mL) and water(0.153 mL) were added. The vial was sealed and heated at 50° C.overnight. The mixture was then cooled to room temperature and directlypurified via silica gel chromatography (0-100% ethyl acetate/hexanes) toafford4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(1-phenylethenyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrileas a yellow solid. MS ESI calcd. for C₂₈H₂₆ClN₅ [M+H]⁺ 468, found 468.

Step 2:4-(5-Chloropyridin-3-yl)-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-2-(1-phenylethenyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamidewas prepared in analogy to Example 2.1, Step 5 and starting from4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(1-phenylethenyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ESI calcd. for C₂₈H₂₉ClN₆O [M+H]⁺501, found 501.

Step 3:3-[4-(5-Chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(1-phenylethenyl)-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one(TFA salt) was prepared in analogy to Example 2.1, Step 6 and startingfrom4-(5-chloropyridin-3-yl)-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-2-(1-phenylethenyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamide.MS ESI calcd. for C₂₉H₂₇ClN₆O₂ [M+H]⁺ 527, found 527. ¹H NMR (500 MHz,DMSO-d₆) δ 12.98 (s, 1H), 8.94 (s, 1H), 8.83 (s, 1H), 8.48 (s, 1H), 8.34(s, 1H), 7.47-7.46 (m, 2H), 7.41-7.40 (m, 3H), 6.40 (s, 1H), 5.90 (s,1H), 3.67 (d, J=6.5 Hz, 2H), 1.33-1.30 (m, 2H), 0.99-0.92 (m, 1H),0.88-0.78 (m, 1H), 0.65-0.63 (m, 4H), 0.62-0.58 (m, 1H), 0.48-0.32 (m,4H).

Example 9.23-{4-(5-chloropyridin-3-yl)-2-(2-methoxy-1-phenylethyl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one

3-[4-(5-Chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(1-phenylethenyl)-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one(Example 9.1, 130 mg, 0.247 mmol) was taken up in methanol (1.644 mL) atroom temperature, and sodium methoxide (1.2 mL of 25 wt % in methanol,5.25 mmol) was added. The mixture was capped and heated to 75° C. for 24hours. The mixture was cooled to room temperature, quenched withsaturated aqueous ammonium chloride, and extracted with ethyl acetate.The organic layer was dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. The resulting residue was purifiedvia automated reverse phase HPLC (methanol/water+0.1% TFA modifier) toafford3-{4-(5-chloropyridin-3-yl)-2-(2-methoxy-1-phenylethyl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(TFA salt) as a white solid. MS ESI calcd. for C₃₀H₃₁ClN₆O₃ [M+H]⁺ 559,found 559. ¹H NMR (500 MHz, DMSO-d₆) δ 12.91 (s, 1H), 8.83 (s, 2H), 8.40(s, 1H), 8.32 (s, 1H), 7.58-7.48 (m, 2H), 7.31-7.25 (m, 3H), 4.80-4.75(m, 1H), 4.21-4.15 (m, 1H), 3.90-3.80 (m, 3H), 3.25 (s, 3H), 1.42-1.35(m, 1H), 1.29-1.20 (m, 2H), 1.04-0.94 (m, 1H), 0.75-0.64 (m, 5H),0.40-0.29 (m, 4H).

Example 9.153-{4-(5-chloropyridin-3-yl)-2-[2-methoxy-1-(methoxymethyl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one

Step 1: A slurry of sodium iodide (20.07 g, 133.9 mmol) in acetonitrile(100 mL) was cooled to 0° C. Trimethylsilyl chloride (17 mL, 133.9 mmol)was added dropwise over a period of 5 minutes followed by water (1.0 mL,53.56 mmol) and stirred for 10 minutes. Prop-2-yn-1-ol (5.0 g, 89.3mmol) was added at 0° C. and the reaction mixture was slowly warmed toroom temperature and stirred for 1 h. The reaction mixture was quenchedwith water and extracted with diethyl ether (15 mL). The organic layerwas washed with saturated sodium thiosulphate solution (10 mL) followedby brine solution (10 mL). The organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure (water bathtemperature <25° C.). The residue was purified by silica gel columnchromatography using 10% diethyl ether/petroleum ether as eluent toyield 2-iodoprop-2-en-1-ol.

Step 2: A stirred solution of 2-iodoprop-2-en-1-ol (24 g, 130.4 mmol) indry dichloromethane (500 mL) was cooled to 0° C. Imidazole (17.75 g,260.9 mmol) was added in several portions, and the mixture was stirredfor 10 minutes. Tert-butyldimethylsilyl chloride (29.49 g, 195.9 mmol)was added in several portions at 0° C., and the reaction mixture wasslowly warmed to room temperature and stirred for 3 h. The reactionmixture was quenched with water (100 mL), and the organic phase wasseparated. The organic phase was washed with brine (100 mL), dried overanhydrous Na₂SO₄, filtered, and concentrated under reduced pressure(water bath temperature <25° C.). The residue was purified by columnchromatography using 100% petroleum ether as eluent to affordtert-butyl((2-iodoallyl)oxy)dimethylsilane.

Step 3: To a stirred solution oftert-butyl((2-iodoallyl)oxy)dimethylsilane (35.0 g, 117.4 mmol) in drytoluene (1000 mL), potassium phenoxide (31.27 g, 234.8 mmol),bis(pinacolato)diboron (44.7 g, 176.2 mmol), and triphenylphospine (3.07g, 11.7 mmol) were added, and the mixture was degassed with argon for 15minutes. PdCl₂(Ph₃P) (4.94 g, 7.06 mmol) was added, and the mixture wasdegassed again for 10 minutes and then heated to 50° C. for 12 h. Thereaction mixture was quenched with water (200 mL) and extracted withethyl acetate (500 mL). The organic layer was washed with brine solution(250 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. Theresidue was purified by silica gel column chromatography using 4% ethylacetate/petroleum ether as eluent to yield tert-butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane. ¹HNMR (400 MHz, CDCl₃): δ 5.97 (d, J=1.7 Hz, 1H), 5.87 (d, J=1.7 Hz, 1H),4.28 (s, 2H), 1.29 (s, 3H), 1.27 (s, 3H), 1.27 (s, 3H), 1.26 (s, 3H),0.92 (s, 9H), 0.15 (s, 6H).

Step 4: To a stirred solution of2-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Preparative Example 3.1; 3.0 g, 6.93 mmol) in 1,4-dioxane (60 mL),tert-butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allypoxy)silane(3.09 g 10.39 mmol), potassium phosphate (2.94 g, 13.86 mmol), and water(6 mL) were added, and the mixture was degassed with argon for 15minutes. PdCl₂(dppf) (0.85 g, 1.04 mmol), was added, and the mixture wasdegassed with argon again for 5 minutes. The reaction was then heated at100° C. for 16 h. The reaction mixture was cooled to room temperature,quenched with water (20 mL), and extracted with ethyl acetate (100 mL).The organic layer was separated, washed with brine (50 mL), dried overanhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by column chromatography using 15% ethylacetate/petroleum ether as eluent to yield2-(3-{[tert-butyl(dimethyl)silyl]oxy}prop-1-en-2-yl)-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ES/APCl calcd. for C₂₉H₃₈ClN₅OSi [M+H]⁺ 536, found 536.

Steps 5 & 6: A stirred solution of2-(3-{[tert-butyl(dimethyl)silyl]oxy}prop-1-en-2-yl)-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(1.2 g, 2.24 mmol) in THF (20 mL) was cooled to 0° C. Tetrabutylammoniumfluoride (3.36 mL, 3.36 mmol, 1M solution in THF) was added dropwiseover a period of 5 minutes, and the reaction mixture was warmed to roomtemperature and stirred for 1 h. The reaction mixture was quenched withwater (10 mL) and extracted with ethyl acetate (15 mL). The organicphase was separated, washed with brine solution (10 mL), dried overanhydrous Na₂SO₄, filtered, and concentrated. The crude4-(5-chloropyridin-3-yl)-2-(3-hydroxyprop-1-en-2-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(0.9 g, 2.14 mmol) was dissolved in dry THF (10 mL) and cooled to 0° C.NaH (0.123 g, 3.12 mmol, 60% in mineral oil) was added in severalportions and stirred for 15 minutes. Methyl iodide (0.16 mL, 2.57 mmol)was added dropwise over a period of 5 minutes, and the reaction mixturewas slowly warmed to room temperature and stirred for 1 h. The reactionmixture was quenched with ice and extracted with ethyl acetate (100 mL).The organic layer was separated, washed with brine (20 mL), dried overanhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography using 15% ethylacetate/petroleum ether as eluent to yield4-(5-chloropyridin-3-yl)-2-(3-methoxyprop-1-en-2-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ES/APCl calcd. for C₂₄H₂₆ClN₅O [M+H]⁺ 436, found 436

Steps 7-9: Using procedures similar to those described in Example 2.1(Step 5 and Step 6) and Example 9.2,4-(5-chloropyridin-3-yl)-2-(3-methoxyprop-1-en-2-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrilewas converted to3-{4-(5-chloropyridin-3-yl)-2-[2-methoxy-1-(methoxymethyl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(TFA salt). MS ES/APCl calcd. for C₂₆H₃₁ClN₆O₄ [M+H]⁺ 527, found 527. ¹HNMR (400 MHz, CDCl₃): δ 9.90 (br s, 1H), 8.76 (s, 1H), 8.65 (s, 1H), δ8.49 (s, 1H), 7.98 (s, 1H), 3.90-3.66 (m, 6H), 3.33 (s, 6H), 3.25-3.11(m, 1H), 1.55 (d, J=11.6 Hz, 2H), 1.26-0.87 (m, 4H), 0.78 (d, J=6.4 Hz,3H), 0.72-0.55 (m, 4H).

Examples in Table 9 (other than examples 9.1, 9.2, and 9.15) wereprepared using procedures which were analogous to those described above.

TABLE 9 FRET IC₅₀ [M + H]+ [M + H]+ Ex. (nM) Structure Chemical NameSalt Calc'd Obsv'd 9.1 4

3-[4-(5- chloropyridin-3-yl)-3- [(trans-4- methylcyclohexyl)methyl]-2-(1-phenylethenyl)-3H- imidazo[4,5-c] pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one TFA 527 527 9.2 2

3-{4-(5- chloropyridin-3-yl)-2- (2-methoxy-1- phenylethyl)-3- [(trans-4-methylcyclohexyl)methyl]- 3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (racemic) TFA 559 559 9.4 2

3-[4-(5- chloropyridin-3-yl)-3- [(trans-4- methylcyclohexyl)methyl]-2-(1- methylidenebutyl)- 3H-imidazo[4,5- c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one TFA 493 493 9.5 2

3-{4-(5- chloropyridin-3-yl)-2- [1-(methoxymethyl) butyl]-3-[(trans-4-methylcyclohexyl) methyl]-3H- imidazo[4,5-c] pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (racemic) 525 525 9.6 2

3-{4-(5- chloropyridin-3-yl)-2- [1- (methoxymethyl) butyl]-3-[(trans-4-methylcyclohexyl) methyl]-3H- imidazo[4,5-c] pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (enantiomer 1) 525 525 9.7 3

3-{4-(5- chloropyridin-3-yl)-2- [1- (methoxymethyl)butyl]-3- [(trans-4-methylcyclohexyl) methyl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (enantiomer 2) 525 525 9.8 7

3-{4-(5- chloropyridin-3-yl)-3- [(trans-4- methylcyclohexyl)methyl]-2-(1-methylethenyl)-3H- imidazo[4,5- c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one 465 465 9.9 11 

3-{4-(5- chloropyridin-3-yl)-2- (2-methoxy-1- methylethyl)-3- [(trans-4-methylcyclohexyl)methyl]- 3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (racemic) 497 497 9.10 9

3-{4-(5- chloropyridin-3-yl)-2- [2-methoxy-1- methylethyl]-3- [(trans-4-methylcyclohexyl) methyl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (enantiomer 1) 497 497 9.11 17 

3-{4-(5- chloropyridin-3-yl)-2- [2-methoxy-1- methylethyl]-3- [(trans-4-methylcyclohexyl) methyl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (enantiomer 2) 497 497 9.12 8

3-{4-(5- chloropyridin-3-yl)-2- (2-ethoxy-1- methylethyl)-3- [(trans-4-methylcyclohexyl) methyl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (racemate) 511 511 9.13 8

3-{4-(5- chloropyridin-3-yl)-3- [(trans-4- methylcyclohexyl)methyl]-2-[1-methyl-2-(1- methylethoxy)ethyl]- 3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one (racemate) 525 525 9.14 6

3-{4-(5- chloropyridin-3-yl)-2- [1-(methoxymethyl) propyl]-3-[(trans-4-methylcyclohexyl)methyl]- 3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (racemate) 511 511 9.15 8

3-{4-(5- chloropyridin-3-yl)-2- [2-methoxy-1- (methoxymethyl)ethyl]-3-[(trans-4- methylcyclohexyl)methyl]- 3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one TFA 527 527 9.16 5

3-{4-(5- chloropyridin-3-yl)-2- [1-(methoxymethyl)- 2-methylpropyl]-3-[(trans-4- methylcyclohexyl)methyl]- 3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one (racemate) TFA 525 525

Example 10.13-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[4-(propan-2-yl)pyridin-2-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one

Step 1: A vial equipped with a stir bar was charged withdi(1-adamantyl)-n-butylphosphine (cataCXium A, Strem) (143.2 mg, 0.40mmol) and palladium acetate (45 mg, 0.20 mmol). Dioxane (2.5 mL) wasadded, and the mixture was degassed with N₂. The vial was then sealedand heated at 50° C. for 30 minutes. The catalyst slurry was then cooledback to room temperature, and 1.5 mL of this catalyst slurry was addedvia syringe to a second vial equipped with a stir bar and containing4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Preparative Example 3.1, Step 2; 100 mg, 0.273 mmol),2-bromo-4-isopropylpyridine (109 mg, 0.547 mmol;purchased fromCombiphos), cesium fluoride (125 mg, 0.82 mmol), and pivalic acid (36.3mg, 0.355 mmol). The reaction was degassed with N₂ for 2 minutes, andthen the vial was sealed and heated at 110° C. for 20 hours. Thereaction was then cooled to room temperature, diluted with hexanes (2mL) and CH₂Cl₂ (2 mL), and loaded directly onto a silica gel column.Purification with 0 to 75% EtOAc/hexanes afforded4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[4-(propan-2-yl)pyridin-2-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ESI calc'd for C₂₈H₂₉ClN₆ [M+H]⁺=485, found=485.

Steps 2 and 3: Using a procedure analagous to that described in Example2.1 (Steps 5 and 6) and starting with4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[4-(propan-2-yl)pyridin-2-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile,3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[4-(propan-2-yl)pyridin-2-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(TFA salt) was prepared. MS ESI calc'd for C₂₉H₃₀ClN₇O₂ [M+H]⁺=544,found=544. ¹H NMR (600 MHz, d6-DMSO) δ 12.95 (s, 1H), 8.93 (s, 1H), 8.39(s, 1H), 8.64 (d, J=5.4 Hz, 1H), 8.46 (s, 1H), 8.35 (s, 1H), 8.18 (s,1H), 7.50 (d, J=5.4 Hz, 1H), 4.54 (bs, 2H), 3.05 (m, 1H), 1.24-1.30 (m,8H), 0.92 (m, 2H), 0.55-0.63 (m, 5H), 0.36-0.45 (m, 4H).

Example 10.1 (Table 10) was prepared as described above.

TABLE 10 FRET IC₅₀ [M + H]+ [M + H]+ Ex. (nM) Structure Chemical NameSalt Calc'd Obsv'd 10.1 4

3-{4-(5- chloropyridin-3-yl)- 3-[(trans-4- methylcyclohexyl)methyl]-2-[4-(1- methylethyl)pyridin- 2-yl]-3H- imidazo[4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one TFA 544 544

Example 11.13-{7-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one

Step 1:4-(5-Chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Example 2.1, Step 4; 180 mg, 0.342 mmol) was taken up in THF (3415 μl)and cooled to −78° C. Lithium magnesium2,2,6,6-tetramethylpiperidin-1-ide dichloride (1 M solution inTHF/toluene, 683 μl, 0.683 mmol) was added, and the mixture was stirredat −78° C. for 45 minutes.1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (244 mg, 0.854 mmol) wasthen added. The cooling bath was removed, and the solution warmed toroom temperature and stirred for 60 minutes. The mixture was thendiluted with ethyl acetate and washed with sodium thiosulfate (2×) andbrine (1×). The organic layer was dried over magnesium sulfate,filtered, and concentrated. The resulting residue was purified viasilica gel chromatography (0-100% ethyl acetate/hexanes) to afford7-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrileas a white solid that was contaminated with unreacted starting material.MS ESI calc'd. for C₃₀H₃₀BrClN₆O [M+1]⁺, [M+3]⁺ 605, 607, found 605,607.

Step 2:7-Bromo-4-(5-chloropyridin-3-yl)-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carboximidamidewas prepared in analogy to Example 2.1, Step 5 using7-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(140 mg, 0.231 mmol) as starting material. MS ESI calc'd. forC₃₀H₃₃BrClN₇O₂ [M+1]⁺, [M+3]⁺638, 640, found 638, 640.

Step 3:3-{7-Bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-onewas prepared in analogy to Example 2.1, Step 6 using7-bromo-4-(5-chloropyridin-3-yl)-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide(148 mg, 0.231 mmol) as starting material and mass guided reverse phaseHPLC (acetonitrile/water+0.1% TFA modifier) for purification. Desiredfractions were then diluted with ethyl acetate, washed with saturatedaqueous sodium bicarbonate, dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. MS ESI calc'd. for C₃₁H₃₁BrClN₇O₃[M+1]⁺, [M+3]⁺ 664, 666, found 664, 666. ¹H NMR (500 MHz, DMSO-d₆) δ12.72 (s, 1H), 8.89 (s, 1H), 8.80 (d, J=2.5 Hz, 1H), 8.44 (s, 1H), 7.47(d, J=7.5 H, 2H), 7.29-7.26 (m, 2H), 7.23-7.20 (m, 1H), 4.92-4.90 (m,1H), 4.04-3.99 (m, 1H), 3.96-3.86 (m, 3H), 3.82-3.77 (m, 1H), 3.63-3.55(m, 2H). 3.38-3.31 (m, 1H), 1.39-1.34 (m, 2H), 1.10-1.01 (m, 1H),0.84-0.54 (m, 2H), 0.68 (d, J=6.5 Hz, 3H), 0.66-0.56 (m, 2H), 0.44-0.27(m, 3H).

Example 11.23-{7-chloro-4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one

Step 1: To a −78° C. solution of4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Example 3.2, Step 3; 250 mg, 0.509 mmol) in THF (7 mL) was added2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloridecomplex (Aldrich, 1M in THF/toluene) (1.02 mL, 1.02 mmol). The resultingsolution was stirred at −78° C. for 45 minutes, and thenhexachloroethane (301 mg, 1.273 mmol) was added as a solid in oneportion. The reaction was allowed to warm slowly to 10° C. over 2 hoursand then quenched with saturated NH₄Cl (10 mL). EtOAc (75 ml) was added,and the organic layer was washed with water and brine (25 mL each). Theorganic layer was dried over Na₂SO₄, filtered, and concentrated.Purification of the residue on a silica gel column eluting with 0 to 50%EtOAc/DCM afforded7-chloro-4-[5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ESI calc'd for C₂₇H₃₀Cl₂N₆O [M+H]⁺=525, found=525.

Step 2: Hydroxylamine hydrochloride (8.2 mg, 0.118 mmol) was dissolvedin water (600 μL), and sodium bicarbonate (14.9 mg, 0.177 mmol) wasadded. The solution was stirred for 30 minutes, and gas evolved. Thesolution was then added to7-chloro-4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(31 mg, 0.059 mmol) suspended in EtOH (1.2 mL). The reaction vial wassealed and heated to 90° C. for 30 minutes. The reaction was then cooledto room temperature, diluted with EtOAc (40 mL) and washed with water(10 mL) and brine (10 mL). The organic layer was dried over Na₂SO₄,filtered and concentrated. The crude product,7-chloro-4-[5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl-N′-hydroxy-3-Rtrans-4-methylcyclohexyl)methy]-3H-imidazo[4,5-c]pyridine-6-carboximidamide,was used in Step 3. MS ESI calc'd for C₂₇H₃₃Cl₂N₇O₂ [M+H]⁺=558,found=558.

Step 3: To7-chloro-4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]3-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide(33.3 mg, 0.06 mmol) in acetonitrile (2 mL) were added1,1′-carbonyldiimidazole (19.3 mg, 0.119 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.036 mL, 0.238 mmol). The reactionwas stirred at room temperature for 1 hour and then concentrated. Theresidue was purified by mass triggered reverse phase HPLC(C-18) elutingwith acetonitrile/water+0.1% TFA to afford347-chloro-4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(TFA salt). MS ESI calc'd for C₂₈H₃₁Cl₂N₇O₃ [M+H]⁺=584, found=584. ¹HNMR (600 MHz, DMSO-d₆) δ 12.74 (s, 1H), 8.92 (d, J=1.2 Hz, 1H), 8.80 (d,J=2.4 Hz, 1H), 8.46 (m, 1H), 3.94 (d, J=9.6 Hz, 1H), 3.77-3.86 (m, 2H),3.56-3.62 (m, 2H), 3.39 (m, 1H), 3.05 (m, 1H), 2.87 (m, 1H), 2.31 (m,1H), 1.86 (m, 1H), 1.71 (m, 1H), 1.51-1.64 (m, 2H), 1.32-1.41 (m, 2H),1.12 (m, 1H), 1.04 (m, 1H), 0.81 (m, 1H), 0.65-0.74 (m, 6H), 0.46 (m,1H), 0.30-0.42 (m, 2H).

Example 11.33-{4-(5-chloropyridin-3-yl)-7-fluoro-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one

Step 1: A dry vial, under an atmosphere of nitrogen was charged with7-chloro-4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Example 11.2, step 125 mg, 0.048 mmol), CsF (50.6 mg, 0.333 mmol), andDMSO (300 μL). The vial was sealed and heated to 100° C. for 3 hours.The reaction was cooled to room temperature, diluted with EtOAc (25 mL)and washed with water (5 mL) and brine (5 mL). The organic layer wasdried over Na₂SO₄, filtered, and concentrated. The residue was purifiedon a silica gel column with 0 to 100% EtOAc/hexanes to afford a 3:1mixture of4-(5-chloropyridin-3-yl)-7-fluoro-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrileand7-chloro-4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ESI calc'd for C₂₇H₃₀ClFN₆O [M+H]⁺=509, found=509. MS ESI calc'd forC₂₇H₃₀Cl₂N₆O [M+H]⁺=525, found=525.

Step 2: Hydroxylamine hydrochloride (7.5 mg, 0.11 mmol) was dissolved inwater (500 μL), and sodium bicarbonate (13.5 mg, 0.16 mmol) was added.The solution was stirred for 30 minutes and gas evolved. The solutionwas then added to a 3:1 mixture of4-(5-chloropyridin-3-yl)-7-fluoro-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrileand7-chloro-4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(27.5 mg, 0.05 mmol) suspended in EtOH (1 mL). The reaction vial wassealed and heated to 55° C. for 30 minutes. The reaction was then cooledto room temperature, diluted with EtOAc (40 mL) and washed with water(10 mL) and brine (10 mL). The organic layer was dried over Na₂SO₄,filtered and concentrated. The crude 3:1 mixture of products,4-(5-chloropyridin-3-yl)-7-fluoro-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamideand7-chloro-4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide,was used in Step 3. MS ESI calc'd for C₂₇H₃₃ClFNγO₂ [M+H]⁺=542,found=542. MS ESI calc'd for C₂₇H₃₃Cl₂N₇O₂ [M+H]⁺=558, found=558.

Step 3: To 3:1 mixture of4-(5-chloropyridin-3-yl)-7-fluoro-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamideand7-chloro-4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide(33 mg, 0.06 mmol) in acetonitrile (2 mL) was added1,1′-carbonyldiimidazole (19.7 mg, 0.122 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.037 mL, 0.244 mmol). The reactionwas stirred at room temperature for 1 hour and then concentrated. Theresidue was purified by mass triggered reverse phase HPLC(C-18) elutingwith acetonitrile/water+0.1% TFA to afford pure3-{4-(5-chloropyridin-3-yl)-7-fluoro-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(TFA salt). MS ESI calc'd for C₂₈H₃₁ClFNγO₃ [M+H]⁺=568, found=568. ¹HNMR (600 MHz, DMSO-d₆) δ 12.83 (s, 1H), 8.91 (d, J=1.8 Hz, 1H), 8.79 (d,J=2.4 Hz, 1H), 8.43 (m, 1H), 3.94 (d, J=9.6 Hz, 1H), 3.78-3.87 (m, 2H),3.63 (dd, J=14.4, 3.6 Hz, 1H), 3.56 (d, J=12.6 Hz, 1H), 3.39 (m, 1H),3.04 (m, 1H), 2.84 (m, 1H), 2.27 (m, 1H), 1.86 (m, 1H), 1.69 (m, 1H),1.51-1.64 (m, 2H), 1.32-1.41 (m, 2H), 1.12 (m, 1H), 1.04 (m, 1H), 0.80(m, 1H), 0.63-0.74 (m, 6H), 0.47 (m, 1H), 0.29-0.42 (m, 2H).

Example 11.43-{4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-7-methoxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one

Step 1: A vial was charged with7-chloro-4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Example 11.2, step 1; 25 mg, 0.048 mmol), CsF (50.6 mg, 0.333 mmol),and DMSO (500 μL). The vial was sealed and heated to 100° C. for 6 hoursand then water (20 μL) was added and heating at 100° C. was continuedfor an additional 20 hours. The reaction was cooled to room temperature,diluted with EtOAc (40 mL), and washed with water (2×10 mL) and brine(2×10 mL). The organic layer was dried over Na₂SO₄, filtered, andconcentrated. The residue, crude4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-7-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile,was used directly in Step 2. MS ESI calc'd for C₂₇H₃₁ClN₆O₂ [M+H]⁺=507,found=507.

Step 2: To a solution of4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-7-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(24.5 mg, 0.048 mmol) in DMF (2 mL) were added Cs₂CO₃ (31.5 mg, 0.097mmol) and MeI (6 μL, 0.097 mmol). The reaction was stirred at roomtemperature for 15 minutes and then diluted with EtOAc (40 mL) andwashed with water (10 mL) and brine (10 mL). The organic layer was driedover Na₂SO₄, filtered, and concentrated. The residue was purified on asilica gel column with 0 to 100% EtOAc/hexanes to afford4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-7-methoxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ESI calc'd for C₂₈H₃₃ClN₆O₂ [M+H]⁺=521, found=521.

Steps 3 and 4: Using a procedure analagous to that described in Example11.2 (Steps 2 and 3) and starting with4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-7-methoxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile,3-{4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-7-methoxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(TFA salt) was prepared. MS ESI calc'd for C₂₉H₃₄ClN₇O₄ [M+H]⁺=580,found=580. ¹H NMR (600 MHz, DMSO-d₆) δ 12.41 (s, 1H), 8.84 (d, J=1.8 Hz,1H), 8.75 (d, J=2.4 Hz, 1H), 8.37 (m, 1H), 4.38 (s, 3H) 3.93 (d, J=9.6Hz, 1H), 3.77-3.84 (m, 2H), 3.59 (dd, J=14.4, 2.4 Hz, 1H), 3.52 (d,J=12.0 Hz, 1H), 3.38 (m, 1H), 3.01 (m, 1H), 2.82 (m, 1H), 2.27 (m, 1H),1.85 (m, 1H), 1.68 (m, 1H), 1.51-1.64 (m, 2H), 1.32-1.41 (m, 2H), 1.13(m, 1H), 1.04 (m, 1H), 0.80 (m, 1H), 0.63-0.76 (m, 6H), 0.45 (m, 1H),0.31-0.42 (m, 2H).

Example 11.53-{4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-7-methyl-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one

Step 1: To a −78° C. solution of4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Example 3.2, Step 3; 300 mg, 0.611 mmol) in THF (8 mL) was added2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloridecomplex (Aldrich, 1M in THF/toluene) (1.22 mL, 1.22 mmol). The resultingyellow solution was stirred at −78° C. for 45 minutes, and then1,3-dibromo-5,5-dimethylhydantoin (437 mg, 1.527 mmol) was added as asolid in one portion. The reaction was allowed to warm slowly to 0° C.over 90 minutes and then quenched with saturated NH₄Cl (10 mL). EtOAc(75 ml) was added, and the organic layer was washed with water and brine(25 mL each). The organic layer was dried over Na₂SO₄, filtered, andconcentrated. Purification of the residue on a silica gel column elutingwith 0 to 50% EtOAc/DCM afforded7-bromo-4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ESI calc'd for C₂₇H₃₀BrClN₆O [M+H]⁺=571, found=571.

Step 2: A vial was charged with7-bromo-4(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(40 mg, 0.07 mmol), trimethylboroxine (10 μL, 0.07 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5 mg, 0.007mmol), K₃PO₄ (37.2 mg, 0.175 mmol), dioxane (0.8 mL), and water (0.2mL). The mixture was sparged with N₂, the vial was sealed, and thereaction was heated at 100° C. for 90 minutes. The reaction was thencooled to room temperature, diluted with EtOAc (40 mL), and washed withwater (10 mL) and brine (10 mL). The organic layer was dried overNa₂SO₄, filtered, and concentrated. The residue was purified on a silicagel column with 0 to 100% EtOAc/hexanes to afford4(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-7-methyl-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ESI calc'd for C₂₈H₃₃ClN₆O [M+H]⁺=505, found=505.

Steps 3 and 4: Using a procedure analogous to that described in Example11.2 (Steps 2 and 3) and starting with4-[5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-7-methyl-3-(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile,3-{4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-7-methyl-34(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(TFA salt) was prepared. MS ESI calc'd for C₂₉H₃₄ClN₇O₃ [M+H]⁺=564,found=564. ¹H NMR (600 MHz, DMSO-d₆) δ 12.56 (s, 1H), 8.90 (s, 1H), 8.77(d, J=2.4 Hz, 1H), 8.44 (s, 1H), 3.93 (d, J=9.6 Hz, 1H), 3.77-3.86 (m,2H), 3.63 (dd, J=14.4, 3.0 Hz, 1H), 3.52 (d, J=12.0 Hz, 1H), 3.38 (m,1H), 3.02 (m, 1H), 2.83 (m, 1H), 2.74 (s, 3H), 2.30 (m, 1H), 1.85 (m,1H), 1.69 (m, 1H), 1.51-1.63 (m, 2H), 1.30-1.41 (m, 2H), 1.12 (m, 1H),1.04 (m, 1H), 0.78 (m, 1H), 0.59-0.72 (m, 6H), 0.49 (d, J=12 Hz, 1H),0.28-0.38 (m, 2H).

Example 11.64-(5-chloropyridin-3-yl)-7-(dimethylamino)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboxylicacid

Step 1: A dry vial, under an atmosphere of nitrogen, was charged with7-chloro-4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Example 11.2, step 1; 50 mg, 0.095 mmol), CsF (101 mg, 0.666 mmol),dimethylamine (0.476 mL of a 2M solution in THF, 0.952 mmol) and DMSO (1mL). The vial was sealed and heated to 100° C. for 8 hours. The reactionwas cooled to room temperature, diluted with EtOAc (25 mL) and washedwith water (5 mL) and brine (5 mL). The organic layer was dried overNa₂SO₄, filtered, and concentrated. The residue was purified on a silicagel column with 0 to 100% EtOAc/hexanes to afford4-(5-chloropyridin-3-yl)-7-(dimethylamino)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ESI calc'd for C₂₉H₃₆ClN₇O [M+H]⁺=534, found=534.

Step 2: To a suspension of4-(5-chloropyridin-3-yl)-7-(dimethylamino)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(31.8 mg, 0.06 mmol) in EtOH (1 mL) was added NaOH (0.2 mL of a 5M aq.solution, 1 mmol). The reaction was heated at 70° C. for 60 hours andthen cooled to room temperature. HOAc (60 μL, 1 mmol) was added followedby DMSO (1.5 mL). After sonication and filtration to remove solids, thefiltrate was purified by mass triggered reverse phase HPLC(C-18) elutingwith acetonitrile/water+0.1% TFA to afford4-(5-chloropyridin-3-yl)-7-(dimethylamino)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboxylicacid (TFA salt). MS ESI calc'd for C₂₆H₃₇ClN₆O₃ [M+H]⁺=553, found=553.¹H NMR (600 MHz, DMSO-d₆) δ 8.75-8.77 (m, 2H), 8.27 (m, 1H), 3.93 (dd,J=12.0, 1.8 Hz, 1H), 3.75-3.81 (m, 2H), 3.47-3.52 (m, 2H), 3.38 (m, 1H),3.15 (s, 6H), 3.03 (m, 1H), 2.81 (m, 1H), 2.26 (m, 1H), 1.85 (m, 1H),1.69 (m, 1H), 1.51-1.63 (m, 2H), 1.31-1.41 (m, 2H), 1.13 (m, 1H), 1.05(m, 1H), 0.83 (m, 1H), 0.64-0.73 (m, 6H), 0.34-0.46 (m, 3H).

The examples in Table 11 were prepared as described above.

TABLE 11 FRET IC₅₀ [M + H]+ [M + H]+ Ex. (nM) Structure Chemical NameSalt Calc'd Obsv'd 11.1 2

3-{7-bromo-4-(5- chloropyridin-3-yl)-3- [(trans-4- methylcyclohexyl)methyl]-2-[(3R)-3- phenylmorpholin-4- yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one 664 664 11.2 1

3-{7-chloro-4-(5- chloropyridin-3-yl)-2- [(4aR,7aR)- hexahydrocyclopenta[b][1,4]oxazin- 4(4aH)-yl]-3-[(trans- 4-methylcyclohexyl) methyl]-3H-imidazo[4,5-c] pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one TFA 584 584 11.31

3-{4-(5- chloropyridin-3-yl)-7- fluoro-2-[(4aR,7aR)- hexahydrocyclopenta[b][1,4]oxazin- 4(4aH)-yl]-3-[(trans- 4- methylcyclohexyl) methyl]-3H-imidazo[4,5-c] pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one TFA 568 568 11.41

3-{4-(5- chloropyridin-3-yl)-2- [(4aR,7aR)- hexahydrocyclopenta[b][1,4]oxazin- 4(4aH)-yl]-7- methoxy-3-[trans-4- methylcyclohexyl)methyl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one TFA580 580 11.5 2

3-{4-(5- chloropyridin-3-yl)-2- [(4aR,7aR)- hexahydrocyclopenta[b][1,4]oxazin- 4(4aH)-yl]-7-methyl- 3-[(trans-4- methylcyclohexyl)methyl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one TFA564 564 11.6 24 

4-(5-chloropyridin-3- yl)-7- (dimethylamino)-2- [(4aR,7aR)-hexahydrocyclopenta [b][1,4]oxazin- 4(4aH)-yl]-3-[(trans-4-methylcyclohexyl) methyl]-3H- imidazo[4,5-c] pyridine-6- carboxylicacid TFA 553 553

Examples 12.1 and 12.2 3-{4-(5-chloropyridin-3-yl)-2-[(2R orS)-1-methoxypropan-2-yl]-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-oneand 3-{4-(5-chloropyridin-3-yl)-2-[(2S orR)-1-methoxypropan-2-yl]-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one

Step 1: A vial was charged with the faster eluting enantiomer(enantiomer 1) of 2-bromo-4-(5-chloropyridin-3-yl)-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Example 4.1, Step 3; 150 mg, 0.33 mmol), potassium phosphate (208 mg,0.98 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (23.9 mg, 0.033 mmol). The tube was evacuated and backfilled withargon (3×). Fully degassed dioxane (1.5 mL) and water (0.15 mL) wereadded, followed by4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.078 mL,0.392 mmol). The vial was sealed and heated to 50° C. for 16 hours. Thereaction mixture was cooled to room temperature and partitioned betweenwater and ethyl acetate. The organic layer was dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel chromatography (0-100% ethyl acetate/hexanes,linear gradient) to afford 4-(5-chloropyridin-3-yl)-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-2-(prop-1-en-2-yl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ESI calc'd. for C₂₄H₂₆ClN₅ [M+H]⁺ 420, found 420.

Step 2: Hydroxylamine hydrochloride (37.7 mg, 0.54 mmol), sodiumbicarbonate (68.4 mg, 0.81 mmol), and water (0.54 mL) were combined in avial and stirred for 15 minutes. This solution was added to a vialcontaining 4-(5-chloropyridin-3-yl)-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-2-(prop-1-en-2-yl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile(114 mg, 0.27 mmol) dissolved in ethanol (1.3 mL). The mixture wassealed and heated at 100° C. for 1 hour. The reaction was cooled to roomtemperature, quenched with water, and extracted with ethyl acetate (2×).The combined organic layers were dried over sodium sulfate, filtered,and concentrated to afford 4-(5-chloropyridin-3-yl)-N-hydroxy-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-2-(prop-1-en-2-yl)-3H-imidazo[4,5-c]pyridine-6-carboximidamide.MS ESI calc'd. for C₂₄H₂₉ClN₆O [M+H]⁺ 453, found 453.

Step 3: To a solution of 4-(5-chloropyridin-3-yl)-N-hydroxy-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-2-(prop-1-en-2-yl)-3H-imidazo[4,5-c]pyridine-6-carboximidamide(109 mg, 0.24 mmol) and 1,1′-carbonyldiimidazole (42.9 mg, 0.26 mmol)dissolved in acetonitrile (1.6 mL) was added1,8-diazabicyclo[5.4.0]undec-7-ene (0.144 mL, 0.96 mmol). The reactionmixture was stirred at room temperature for 1 hour. The reaction wasdiluted with water and extracted with dichloromethane. The organic layerwas dried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by silica gel chromatography (0-15%methanol/dichloromethane, linear gradient) to afford3-[4-(5-chloropyridin-3-yl)-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-2-(prop-1-en-2-yl)-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one.MS ESI calc'd. for C₂₅H₂₇ClN₆O₂ [M+H]⁺ 479, found 479.

Step 4: 3-[4-(5-chloropyridin-3-yl)-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-2-(prop-1-en-2-yl)-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one(107 mg, 0.22 mmol) was taken up in methanol (1.1 mL) at roomtemperature, and sodium methoxide (25 wt % in methanol, 1.3 mL, 5.58mmol) was added. The reaction was capped and heated to 75° C. for threedays. The mixture was cooled to room temperature and quenched withsaturated aqueous ammonium chloride. The mixture was extracted withethyl acetate, and the organic layer was dried over sodium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified by mass triggered, reverse phase (C-18) preparative HPLC(acetonitrile:water: 0.1% v/v trifluoroacetic acid modifier) to afford3-{4-(5-chloropyridin-3-yl)-2-[(2RS)-1-methoxypropan-2-yl]-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-oneas a TFA salt. MS ESI calc'd. for C₂₆H₃₁ClN₆O₃ [M+H]⁺ 511, found 511.The diastereomers of3-{4-(5-chloropyridin-3-yl)-2-[(2RS)-1-methoxypropan-2-yl]-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-onewere separated by chiral supercritical fluid chromatography (ChiralpakAD-H, 21×250 mm, 20% ethanol in CO₂) to afford3-{4-(5-chloropyridin-3-yl)-2-[(2R or S)-1-methoxypropan-2-yl]-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-oneand 3-{4-(5-chloropyridin-3-yl)-2-[(2S orR)-1-methoxypropan-2-yl]-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one.

Faster eluting diastereomer: MS ESI calc'd. for C₂₆H₃₁ClN₆O₃ [M+H]⁺ 511,found 511. ¹H NMR (500 MHz, DMSO-d₆) δ 12.89 (s, 1H), 8.84 (d, J=2.4,1H), 8.81 (s, 1H), 8.35 (s, 1H), 8.20 (s, 1H), 3.84 (t, J=8.9, 1H), 3.78(dd, J=7.3, 10.8, 1H), 3.64 (dd, J=5.2, 8.7, 1H), 3.61-3.51 (m, 1H),3.17 (s, 3H), 1.90-1.80 (m, 1H), 1.76-1.69 (m, 1H), 1.56 (s, 1H), 1.53(d, J=7.1, 3H), 1.34 (d, J=12.0, 1H), 1.25 (d, J=6.7, 3H), 0.98 (s, 1H),0.81-0.74 (m, 1H), 0.73 (d, J=6.4, 3H), 0.63-0.49 (m, 2H), 0.25-0.10 (m,2H).Slower eluting diastereomer: MS ESI calc'd. for C₂₆H₃₁ClN₆O₃ [M+H]⁺ 511,found 511. ¹H NMR (500 MHz, DMSO-d₆) δ 12.90 (s, 1H), 8.85 (d, J=2.4,1H), 8.80 (d, J=1.6, 1H), 8.36 (d, J=2.0, 1H), 8.21 (s, 1H), 3.79-3.69(m, 2H), 3.64-3.50 (m, 2H), 3.21 (s, 3H), 1.79-1.68 (m, 2H), 1.59-1.53(m, 1H), 1.51 (d, J=7.1, 3H), 1.39 (d, J=11.9, 1H), 1.26 (d, J=6.5, 3H),1.01 (s, 1H), 0.90-0.78 (m, 1H), 0.74 (d, J=6.5, 3H), 0.66-0.56 (m, 1H),0.52-0.45 (m, 1H), 0.38-0.29 (m, 1H), 0.24-0.15 (m, 1H).

Examples 12.3 and 12.4 were prepared in the same manner as Examples 12.1and 12.2, starting from the slower eluting enantiomer (enantiomer 2) of2-bromo-4-(5-chloropyridin-3-yl)-3-[(1S orR)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Example 4.1, Step 3).

TABLE 12 FRET [M + H]+ [M + H]+ Ex. IC₅₀ (nM) Structure Chemical NameSalt Calc'd Obsv'd 12.1  1

3-{4-(5- chloropyridin-3-yl)-2- [(2R or S)-1- methoxypropan-2-yl]-3-[(1R or S)-1- (trans-4- methylcyclohexyl)ethyl]- 3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one (stereoisomer 1) 511 511 12.2 1

3-{4-(5- chloropyridin-3-yl)-2- [(2S or R)-1- methoxypropan-2-yl]-3-[(1R or S)-1- (trans-4- methylcyclohexyl)ethyl]- 3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one (stereoisomer 2) 511 511 12.3 44

3-{4-(5- chloropyridin-3-yl)-2- [(2R or S)-1- methoxypropan-2-yl]-3-[(1S or R)-1- (trans-4- methylcyclohexyl)ethyl]- 3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one (stereoisomer 3) 511 511 12.4161

3-{4-(5- chloropyridin-3-yl)-2- [(2S or R)-1- methoxypropan-2-yl]-3-[(1S or R)-1- (trans-4- methylcyclohexyl)ethyl]- 3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one (stereoisomer 4) 511 511

Example 13.14-(5-chloropyridin-3-yl)-2-(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-3-((trans-4-methylcyclohexyl)methyl)-N-(methylsulfonyl)-3H-imidazo[4,5-c]pyridine-6-carboxamide

To a stirred mixture of4-(5-chloropyridin-3-yl)-2-((4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboxylicacid (Example 3.55, prepared from Example 3.2, Step 3 using a procedureanalogous to that described in Example 1.1, Step 5; 93 mg, 0.183 mmol)and methanesulfonamide (34.8 mg, 0.366 mmol) in DCM (2 ml) were addedDMAP (44.7 mg, 0.366 mmol) and EDC (70.2 mg, 0.366 mmol). The reactionmixture was allowed to stir at room temperature under nitrogenovernight. The reaction mixture was diluted with DCM and washed withwater and aq. 2N HCl before being dried over sodium sulfate, filtered,and concentrated. The residue was purified by mass triggered, reversephase (C-18) preparative HPLC (acetonitrile:water: 0.1% v/vtrifluoroacetic acid modifier) to afford4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-3-((trans-4-methylcyclohexyl)methyl)-N-(methylsulfonyl)-3H-imidazo[4,5-c]pyridine-6-carboxamideas a TFA salt. MS ESI calc'd. for C₂₈H₃₆ClN₆O₄S [M+H]⁺ 587, found 587.¹H NMR (500 MHz, DMSO-d₆) δ 8.99 (s, 1H); 8.82 (s, 1H); 8.57 (s, 1H);8.20 (s, 1H); 3.96 (d, J=14.9 Hz, 1H); 3.79-3.88 (m, 2H); 3.53-3.61 (m,2H); 3.39-3.41 (m, 1H); 3.38 (s, 3H); 3.03 (m, 1H); 2.81-2.87 (m, 1H);2.24-2.30 (m, 1H); 1.84-1.89 (m, 1H); 1.52-1.71 (m, 3H); 1.34-1.43 (m,2H); 1.01-1.15 (m, 2H); 0.76-0.84 (m, 1H); 0.66-0.72 (m, 5H); 0.59-0.61(m, 1H); 0.46-0.48 (m, 1 H); 0.35 (q, J=12.4 Hz, 2H).

Example 13.34-(5-chloropyridin-3-yl)-N-methyl-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carboxamide

To a solution of4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carboxylicacid (Example 3.22, prepared from Example 2.1, Step 4 using a proceduresimilar to that described for Example 1.1, Step 5; 50 mg, 0.09 mmol) inDMF (2.0 mL) were added HATU (15 mg, 0.11 mmol), DIPEA (0.03 mL, 0.18mmol), and 2.0 M methylamine in MeOH (0.09 mL, 0.18 mmol) at roomtemperature. After being stirred for 2 hours, the reaction mixture wasdiluted with H₂O (10 mL), the aqueous layer was extracted with EtOAc andthen the organic layer was washed with water and brine, dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo. Purification ofthe residue on a silica gel column (0 to 10% MeOH/CH₂Cl₂) afforded4-(5-chloropyridin-3-yl)-N-methyl-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carboxamide.¹H NMR (300 MHz, CD₃OD) δ 8.71 (d, J=2.1 Hz, 1H), 8.66 (s, 1H),8.17-8.19 (m, 2H) 7.40-7.42 (m, 2H), 7.24-7.26 (m, 3H), 4.66-4.69 (m,1H), 3.98-4.06 (m, 4H), 3.66-3.75 (m, 2H), 3.41-3.50 (m, 2H), 3.48 (s,3H), 1.28-1.43 (m, 2H), 1.10-1.19 (m, 1H), 0.82-0.99 (m, 2H), 0.74 (d,J=6.3 Hz, 3H) 0.61-0.65 (m, 3H), 0.41-0.45 (m, 2H). MS APCl calc'd. forC₃₁H₃₅ClN₆O₂ [M+H]⁺ 559, found 559.

Example 13.5N-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}methanesulfonamide

Step 1: To a solution of4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carboxylicacid (Example 3.22, prepared from Example 2.1, Step 4 using a proceduresimilar to that described for Example 1.1, Step 5; 500 mg, 0.91 mmol) inDMF (6 mL) was added TEA (0.2 mL, 1.83 mmol), and the reaction wasdeoxygenated by purging with nitrogen for 5 minutes. To this reactionmixture was added diphenyl phosphoryl azide (0.4 mL, 1.83 mmol) and thereaction flask was sealed. The mixture was stirred at rt for 1 h andthen H₂O (2 mL) was added. Again, the reaction flask was sealed and thereaction was heated at 90° C. for 1.5 h. The reaction was then dilutedwith water and EtOAc. The organic layer was separated and washed withwater and brine. The organic layer was dried over anhydrous Na₂SO₄,filtered, and concentrated. The residue was purified by silica gelchromatography (2% MeOH/CH₂Cl₂) to yield4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-amine.MS ES/APCl calc'd. for C₂₉H₃₃ClN₆O [M+H]⁺ 517, found 517.

Step 2: To a solution of4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-amine(70 mg, 0.13 mmol) in dichloromethane (2.0 mL) was added TEA (27 mg,0.27 mmol) at 0° C. followed by slow addition of methane sulfonylchloride (15 mg, 0.13 mmol). The reaction was warmed slowly to roomtemperature and stirred for 2 h. The reaction was then diluted withCH₂Cl₂ (70 mL) and water (10 mL). The organic layer was separated,washed with saturated brine solution (2×20 mL), dried over anhydrousNa₂SO₄, filtered, and concentrated. The residue was dissolved in THF (1mL), MeOH (1 mL), and H₂O (0.5 mL), and then LiOH (20 mg, 0.48 mmol) wasadded. The reaction was stirred at room temperature for 1 h. Thereaction was then concentrated under reduced pressure. The residue waspurified by silica gel chromatography (90% EtOAc/petroleum ether). Theisolated product was further purified by preparative HPLC(acetonitrile:water: 0.1% v/v trifluoroacetic acid modifier) to affordN-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}methanesulfonamide(TFA salt). MS ES/APCl calc'd. for C₃₀H₃₆ClN₆O₃S [M+H]⁺ 595, found 595.¹H NMR (400 MHz, DMSO-d₆): δ 10.26 (bs, 1H), 8.77 (d, J=2.0 Hz, 2H),8.23 (t, J=2.0 Hz, 1H), 7.43 (d, J=7.2 Hz, 2H), 7.29-7.21 (m, 3H), 6.99(s, 1H), 4.75 (t, J=5.2 Hz, 1H), 3.92-3.88 (m, 4H), 3.75-3.70 (m, 1H),3.54-3.49 (m, 2H), 3.26 (s, 3H), 3.25-3.20 (m, 1H), 1.41-1.35 (m, 2H),1.08-1.07 (m, 1H), 0.76-0.74 (m, 3H), 0.70 (d, J=6.8 Hz, 3H), 0.58-0.55(m, 1H), 0.50-0.47 (m, 1H), 0.40-0.27 (m, 2H).

Examples in Table 13 (other than Examples 13.1, 13.3, and 13.5) wereprepared using procedures that were analogous to those described above.

TABLE 13 FRET IC₅₀ [M + H]+ [M + H]+ Ex. (nM) Structure Chemical NameSalt Calc'd Obsv'd 13.1  1

4-(5-chloropyridin-3-yl)- 2-[(4aR,7aR)- hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3- [(trans-4- methylcyclohexyl)methyl]-N-(methylsulfonyl)- 3H-imidazo[4,5- c]pyridine-6- carboxamide TFA 587587 13.2  2

4-(5-chloropyridin-3-yl)- N-(dimethylsulfamoyl)- 2-[(4aR,7aR)-hexahydrocyclopenta[b] [1,4]oxazin-4(4aH)-yl]-3- [(trans-4-methylcyclohexyl)methyl]- 3H-imidazo[4,5- c]pyridine-6- carboxamide TFA616 616 13.3 160

4-(5-chloropyridin-3-yl)- N-methyl-3-[(trans-4-methylcyclohexyl)methyl]-2- [(3R)-3-phenylmorpholin- 4-yl]-3H-imidazo[4,5-c]pyridine-6- carboxamide 559 559 13.4 175

4-(5-chloropyridin-3-yl)- N,N-dimethyl-3-[(trans-4-methylcyclohexyl)methyl]- 2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5- c]pyridine-6-carboxamide 573 573 13.5 122

N-{4-(5-chloropyridin-3- yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-[(3R)-3- phenylmorpholin-4-yl]- 3H-imidazo[4,5- c]pyridin-6-yl}methanesulfonamide TFA 595 595

Example 14.14-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-6-(1H-tetrazol-5-yl)-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridine

A vial equipped with a stir bar was charged with4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Example 3.3, Step 1) (67 mg, 0.133 mmol), sodium azide (87 mg, 1.332mmol), and ammonium chloride (72.0 mg, 1.345 mmol). DMF (1.3 mL) wasadded, and the mixture was degassed with N₂. The vial was then sealedand heated at 120° C. for 16 hours. The reaction was then cooled to roomtemperature, diluted with EtOAc, and washed with water and brine. Theorganic layer was dried over Na₂SO₄, filtered, and concentrated.Purification of the residue by mass triggered reverse phase HPLC(C-18),eluting with acetonitrile/water containing 0.1% TFA afforded4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-6-(1H-tetrazol-5-yl)-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridine(TFA salt). MS ESI calc'd. for C₂₅H₂₇ClF₃N₉ [M+H]⁺546, found 546. ¹H NMR(600 MHz, CD₃OD) δ 8.86 (d, J=1.5, 1H), 8.74 (d, J=2.2 Hz, 1H), 8.38 (t,J=2.1 Hz, 1H), 8.26 (s, 1H), 5.36-5.27 (m, 1H), 3.92 (dd, J=9.0, 14.7Hz, 1H), 3.87-3.79 (m, 1H), 3.73-3.66 (m, 1H), 3.61 (dd, J=5.5, 14.7 Hz,1H), 2.48-2.36 (m, 1H), 2.21-2.10 (m, 2H), 2.08-1.98 (m, 1H), 1.45 (dd,J=1.4, 11.7 Hz, 2H), 1.23-1.13 (m, 1H), 1.13-1.04 (m, 1H), 1.02-0.94 (m,1H), 0.72 (d, J=6.6 Hz, 3H), 0.71-0.56 (m, 3H), 0.57-0.46 (m, 2H).

Example 14.25-{4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-2-methyl-1,2-dihydro-3H-1,2,4-triazol-3-one

Step 1: Sodium methoxide (5.20 mg, 0.096 mmol) was added to a solutionof4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Example 3.1, Step 1; 150 mg, 0.321 mmol) in methanol (321 μL), and thevial was sealed and allowed to stir at ambient temperature overnight.The reaction was concentrated to afford crudemethyl-4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-carbimidate.MS ESI calc'd. for C₂₆H₃₂ClFN₆O [M+H]⁺ 499, found 499. This material wastaken on to Step 2 without further purification.

Step 2: Methylhydrazine (79.2 μL, 1.502 mmol) was added to a solution ofcrudemethyl-4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-carbimidate(75 mg, 0.150 mmol) in methanol (1503 μL) in a vial, and the reactionwas sealed and stirred at 50° C. for 16 hr. The reaction was cooled toroom temperature, diluted with EtOAc, and washed with water and brine.The organic layer was dried over Na₂SO₄, filtered, and concentrated toafford crude4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-N′-methyl-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-carboximidohydrazide.MS ESI calc'd. for C₂₆H₃₄ClFN₈ [M+H]⁺ 513, found 513. This material wastaken on to Step 3 without further purification.

Step 3: CDI (26.5 mg, 0.164 mmol) and DBU (99 μL, 0.655 mmol) were addedto a solution of crude4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-N′-methyl-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-carboximidohydrazide(56.0 mg, 0.109 mmol) in acetonitrile (1213 μL), and the reaction wasstirred at ambient temperature for 1 hr. Purification by mass triggeredreverse phase HPLC(C-18), eluting with acetonitrile/water containing0.1% TFA afforded impure5-{4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-2-methyl-1,2-dihydro-3H-1,2,4-triazol-3-one(TFA salt). Further purification by PTLC with 5% MeOH/DCM afforded pure5-{4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-2-methyl-1,2-dihydro-3H-1,2,4-triazol-3-one.¹H NMR (600 MHz, CD₃OD) δ 8.82 (d, J=1.8 Hz, 1H), 8.69 (d, J=2.3 Hz,1H), 8.36 (t, J=2.1 Hz, 1H), 7.92 (s, 1H), 4.66 (dd, J=3.7, 9.8 Hz,0.5H), 4.63-4.49 (m, 2H), 4.44 (dd, J=3.1, 9.5 Hz, 0.5H), 3.86 (dd,J=8.5, 14.8 Hz, 1H), 3.73-3.85 (m, 2H), 3.53 (d, J=6.1 Hz, 1H), 3.49 (s,3H), 2.28-2.18 (m, 1H), 2.18-2.08 (m, 1H), 2.07-1.90 (m, 2H), 1.49-1.39(m, 2H), 1.25-1.16 (m, 1H), 1.15-1.01 (m, 1H), 0.99-0.93 (m, 1H), 0.70(dd, J=9.1, 19.3 Hz, 3H), 0.70-0.61 (m, 1H), 0.61-0.46 (m, 4H). MS ESIcalc'd. for C₂₇H₃₂ClFN₈O [M+H]⁺ 539, found 539.

Example 14.35-{4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-2,4-dihydro-3H-1,2,4-triazol-3-one

Step 1: Tert-butyl carbazate (106 mg, 0.802 mmol) and triethylamine (418μL, 3.006 mmol) were added to a solution of crudemethyl-4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-carbimidate(Example 14.2, Step 1; 50 mg, 0.100 mmol) in ethanol (100 μL) in a vial,and the reaction was capped and stirred at ambient temperature for 72hr. The reaction was diluted with EtOAc and washed with water and brine.The organic layer was dried over Na₂SO₄, filtered, and concentrated toafford crude tert-butyl2-[(4-(5-chloropyridin-3-yl)-2-(S)-2-(fluoromethyl)pyrrolidin-1-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)(imino)methyl)hydrazinecarboxylate.MS ESI calc'd. for C₃₀H₄₀ClFN₈O₂ [M+H]⁺ 599, found 599. This materialwas taken on to Step 2 without further purification.

Step 2: A solution of crude tert-butyl2-((4-(5-chloropyridin-3-yl)-2-(S)-2-(fluoromethyl)pyrrolidin-1-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)(imino)methyl)hydrazinecarboxylate(19.0 mg, 0.032 mmol) in acetonitrile (793 μL) was stirred at 80° C. for72 hr. Purification of the reaction by mass triggered reverse phaseHPLC(C-18), eluting with acetonitrile/water containing 0.1% TFA afforded5-{4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-2,4-dihydro-3H-1,2,4-triazol-3-one(TFA salt). ¹H NMR (600 MHz, CD₃OD) δ 8.83 (d, J=1.8 Hz, 1H), 8.72 (d,J=2.3 Hz, 1H), 8.38 (t, J=2.1 Hz, 1H), 7.96 (s, 1H), 4.70 (dd, J=3.3,9.9 Hz, 0.5H), 4.65-4.51 (m, 2H), 4.45 (dd, J=4.1, 9.9 Hz, 0.5H), 3.90(dd, J=8.4, 14.9 Hz, 1H), 3.85-3.74 (m, 2H), 3.55 (dd, J=6.0, 14.9 Hz,1H), 2.32-2.24 (m, 1H), 2.19-2.11 (m, 1H), 2.05-1.93 (m, 2H), 1.50-1.42(m, 2H), 1.27-1.19 (m, 1H), 1.15-1.04 (m, 1H), 1.04-0.97 (m, 1H), 0.73(d, J=6.6 Hz, 3H), 0.72-0.63 (m, 1H), 0.63-0.50 (m, 4H). MS ESI calc'd.for C₂₆H₃₀ClFN₈O [M+H]⁺ 525, found 525.

Example 14.5 methyl4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carboxylate

4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Example 2.1, Step 4; 50 mg, 0.14 mmol) was dissolved in HCl (3 M inMeOH; 10 mL) and stirred at reflux for 4 hours. The reaction was cooledto room temperature, and the solvent was removed under vacuum. Theresidue was partitioned between water and EtOAc. The organic layer wasdried over anhydrous Na₂SO₄, filtered, and concentrated. Purification ofthe residue on a silica gel column (0 to 100% EtOAc/hexanes) affordedmethyl4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carboxylate.¹H NMR (300 MHz, CD₃OD) δ 8.72 (d, J=2.4 Hz, 1H), 8.63 (d, J=1.6 Hz,1H), 8.23 (s, 1H), 8.14 (br s, 1H) 7.41-7.43 (m, 2H), 7.24-7.27 (m, 3H),4.67-4.69 (m, 1H), 3.98-4.06 (m, 4H), 3.97 (s, 3H), 3.69-3.70 (m, 2H),3.31-3.56 (m, 2H), 1.28-1.43 (m, 2H), 1.10-1.19 (m, 1H), 0.82-0.99 (m,2H), 0.74 (d, J=6.3 Hz, 3H) 0.61-0.65 (m, 3H), 0.41-0.45 (m, 2H). MSAPCl calc'd. for C₃₁H₃₄ClN₅O₃ [M+H]⁺ 560, found 560.

Examples in Table 14 (other than Examples 14.1-14.3 and 14.5) wereprepared using procedures that were analogous to those described above.

TABLE 14 FRET IC₅₀ [M + H]+ [M + H]+ Ex. (nM) Structure Chemical NameSalt Calc'd Obsv'd 14.1 <1

4-(5-chloropyridin-3-yl)- 3-[(trans-4- methylcyclohexyl)methyl]-6-(1H-tetrazol-5-yl)- 2-[(2S)-2- (trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5- c]pyridine TFA 546 546 14.2 20

5-{4-(5-chloropyridin-3- yl)-2-[(2S)-2- (fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4- methylcyclohexyl)methyl]- 3H-imidazo[4,5-c]pyridin-6-yl}-2- methyl-1,2-dihydro-3H- 1,2,4-triazol-3-one 539 53914.3 10

5-{4-(5-chloropyridin-3- yl)-2-[(2S)-2- (fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4- methylcyclohexyl)methyl]- 3H-imidazo[4,5-c]pyridin-6-yl}-2,4- dihydro-3H-1,2,4- triazol-3-one TFA 525 525 14.4 <1

4-(5-chloropyridin-3-yl)- 2-[(4aR,7aR)- hexahydrocyclopenta[b][1,4]oxazin-4-(4aH)-yl]- 3-[(trans-4- methylcyclohexyl)methyl]-6-(1H-tetrazol-5-yl)- 3H-imidazo[4,5- c]pyridine TFA 534 534 14.5 28

methyl 4-(5- chloropyridin-3-yl)-3- [(trans-4- methylcyclohexyl)methyl]-2-[(3R)-3- phenylmorpholin-4-yl]- 3H-imidazo[4,5- c]pyridine-6-carboxylate 560 560 14.6 53

ethyl 4-(5- chloropyridin-3-yl)-3- [(trans-4- methylcyclohexyl)methyl]-2-[(3R)-3- phenylmorpholin-4-yl]- 3H-imidazo[4,5- c]pyridine-6-carboxylate 574 574

Preparative Example 15.14-(5-chloropyridin-3-yl)-3-[(1S)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrileand4-(5-chloropyridin-3-yl)-3-[(1R)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile

Racemic4-(5-chloropyridin-3-yl)-3-[(1RS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Example 4.1/4.2, Step 2) was separated into its enantiomers usingchiral supercritical fluid chromatography (Phenomenex, 21×250 mm, 25%methanol in CO₂) to afford4-(5-chloropyridin-3-yl)-3-[(1S)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrileand4-(5-chloropyridin-3-yl)-3-[(1R)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.Faster eluting enantiomer: MS ESI calc'd. for C₂₁H₂₂ClN₅ [M+H]⁺ 380,found 380. ¹H NMR (600 MHz, DMSO-d₆) δ 8.93 (s, 1H), 8.84 (d, J=2.2,1H), 8.77 (d, J=1.5, 1H), 8.56 (s, 1H), 8.33 (t, J=1.7, 1H), 3.69 (m,1H), 1.57-1.28 (m, 7H), 1.11-0.97 (m, 1H), 0.72 (d, J=6.5, 3H),0.70-0.46 (m, 5H). Slower eluting enantiomer: MS ESI calc'd. forC₂₁H₂₂ClN₅ [M+H]⁺ 380, found 380. ¹H NMR (600 MHz, DMSO-d₆) δ 8.93 (s,1H), 8.84 (d, J=2.2, 1H), 8.77 (d, J=1.5, 1H), 8.56 (s, 1H), 8.33 (t,J=1.7, 1H), 3.69 (m, 1H), 1.58-1.28 (m, 7H), 1.11-0.96 (m, 1H), 0.72 (d,J=6.5, 3H), 0.70-0.46 (m, 5H).

Preparative Example 15.2 4-(5-chloropyridin-3-yl)-2-[(1R orS)-1-hydroxyethyl]-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrileand 4-(5-chloropyridin-3-yl)-2-[(1 S or R)-1-hydroxyethyl]-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile

4-(5-chloropyridin-3-yl)-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Preparative Example 15.1, slower eluting enantiomer; 400 mg, 1.053mmol) was dissolved in THF (10.4 mL) and cooled to −78° C. undernitrogen before adding 2,2,6,6-tetramethylpiperidinylmagnesium chloridelithium chloride complex (Aldrich, 1M in THF/toluene, 2.32 mL, 2.32mmol). After stirring at −78° C. for 1 hr, acetaldehyde (190 μL, 3.37mmol) was added, and the reaction was allowed to stir at −78° C. for 1.5hr. The reaction was then quenched with saturated aqueous ammoniumchloride and extracted with EtOAc. The organic layer was dried oversodium sulfate, filtered, and concentrated. The residue was purified bysilica gel chromatography (5-75% EtOAc/DCM) to afford4-(5-chloropyridin-3-yl)-2-[(1R or S)-1-hydroxyethyl]-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrileand 4-(5-chloropyridin-3-yl)-2-[(1 S or R)-1-hydroxyethyl]-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.Faster eluting diastereomer: MS ESI calc'd. for C₂₃H₂₆ClN₅O [M+H]⁺ 424,found 424. Slower eluting diastereomer: MS ESI calc'd. for C₂₃H₂₆ClN₅O[M+H]⁺ 424, found 424.

Example 15.1 3-{4-(5-chloropyridin-3-yl)-2-[(S orR)-cyclopropyl(ethoxy)methyl]-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(stereoisomer 1)

Step 1: 4-(5-chloropyridin-3-yl)-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Preparative Example 15.1, slower eluting enantiomer; 580 mg, 1.53 mmol)was dissolved in THF (15 mL) and cooled to −78° C. under nitrogen.Cyclopropanecarboxaldehyde (0.396 mL, 5.34 mmol) was added, followed by2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloridecomplex (Aldrich, 1M in THF/toluene, 3.05 mL, 3.05 mmol) and thereaction was stirred at −78° C. After 30 minutes, additional2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloridecomplex (Aldrich, 1M in THF/toluene, 1.5 mL, 1.5 mmol) was added, andthe reaction was stirred for a further 30 minutes at −78° C. Thereaction was quenched by pouring it into 30 mL of saturated NH₄Cl. Themixture was extracted with EtOAc (100 mL), and the organic layer waswashed with brine (25 mL). The organic layer was dried over Na₂SO₄,filtered, and concentrated. Purification of the residue on a silica gelcolumn with 0 to 100% EtOAc/DCM afforded a first and second elutingdiastereomer. 4-(5-chloropyridin-3-yl)-2-[(R or Sycyclopropyl(hydroxy)methyl]-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile;Diastereomer 1 (faster eluting): MS ESI calc'd. for C₂₅H₂₈ClN₅O [M+H]⁺450, found 450. 4-(5-chloropyridin-3-yl)-2-[(S orR)cyclopropyl(hydroxy)methyl]-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile;Diastereomer 2 (slower eluting): MS ESI calc'd. for C₂₅H₂₈ClN₅O [M+H]⁺450, found 450.

Step 2: 4-(5-chloropyridin-3-yl)-2-[(S orR)-cyclopropyl(hydroxy)methyl]-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(Diastereomer 2 (slower eluting); 165 mg, 0.367 mmol) was dissolved inTHF (4 mL) and cooled to 0° C. NaH (60%, 29.3 mg, 0.733 mmol) was addedfollowed after 5 minutes by iodoethane. The reaction was allowed to warmto room temperature and stirred for 18 hours. The reaction was thenquenched with saturated NH₄Cl (5 mL) and diluted with EtOAc (50 mL). Theorganic layer was washed with water and brine (15 mL each), dried overNa₂SO₄, filtered, and concentrated. Purification of the residue on asilica gel column with 0 to 60% EtOAc/hexanes afforded4-(5-chloropyridin-3-yl)-2-[(S or R)-cyclopropyl(ethoxy)methyl]-3-[(1RorS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ESI calc'd. for C₂₇H₃₂ClN₅O [M+H]⁺ 478, found 478.

Step 3: Hydroxylamine hydrochloride (38.7 mg, 0.556 mmol) was dissolvedin water (1.5 mL), and sodium bicarbonate (70.1 mg, 0.835 mmol) wasadded. The solution was stirred for 30 minutes, and gas evolved. Thesolution was then added to 4-(5-chloropyridin-3-yl)-2-[(S orR)cyclopropyl(ethoxy)methyl]-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(133 mg, 0.278 mmol) suspended in EtOH (3 mL). The reaction vial wassealed and heated to 60° C. for 1 hour. The reaction was then cooled toroom temperature, diluted with EtOAc (100 mL) and washed with water(2×10 mL) and brine (10 mL). The organic layer was dried over Na₂SO₄,filtered, and concentrated. The crude product,4-(5-chloropyridin-3-yl)-2-[(S orR)-cyclopropyl(ethoxy)methyl]-N-hydroxy-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide,was used in Step 4. MS ESI calc'd for C₂₇H₃₅ClN₆O₂ [M+H]⁺=511,found=511.

Step 4: To 4-(5-chloropyridin-3-yl)-2-[(S orR)-cyclopropyl(ethoxy)methyl]-N-hydroxy-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide(143.2 mg, 0.28 mmol) in acetonitrile (10 mL) were added1,1′-carbonyldiimidazole (91 mg, 0.560 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.169 mL, 1.12 mmol). The reactionwas stirred at room temperature for 1 hour and then diluted with EtOAc(100 mL) and washed with 0.25 M HCl (10 mL) and brine (10 mL). Theorganic layer was dried over Na₂SO₄, filtered, and concentrated. Theresidue was purified by silica gel chromatography with 3:1 hexanes:DCMcontaining 2% MeOH followed by further purification on silica gel with50 to 100% EtOAc/hexanes to afford 3-{4-(5-chloropyridin-3-yl)-2-[(S orR)-cyclopropyl(ethoxy)methyl]-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one.MS ESI calc'd for C₂₈H₃₃ClN₆O₃ [M+H]⁺=537, found=537. ¹H NMR (600 MHz,DMSO-d₆) δ 12.89 (s, 1H), 8.82 (d, J=11.4 Hz, 2H), 8.36 (s, 1H), 8.27(s, 1H), 8.15 (d, J=9.0 Hz, 1H), 3.78 (m, 2H), 3.52 (m, 1H), 0.60-1.74(m, 18H), 0.44-0.56 (m, 2H), 0.24-0.39 (m, 2H), −0.03-0.16 (m, 2H).

Examples in Table 15 (other than Example 15.1) were prepared usingprocedures that were analogous to those described above. Example 15.2was prepared from the faster eluting diastereomer (diastereomer 1) ofEx. 15.1, Step 1. Examples 15.3 and 15.4 were prepared starting from thefaster eluting enantiomer of Preparative Example 15.1. Examples15.5-15.8 were prepared starting from the slower eluting enantiomer ofPreparative Example 15.1.

TABLE 15 FRET IC₅₀ [M + H]+ [M + H]+ Ex. (nM) Structure Chemical NameSalt Calc'd Obsv'd 15.1 <1

3-{4-(5-chloropyridin-3- yl)-2-[(S or R)- cyclopropyl(ethoxy)methyl]-3-[(1R or S)-1- (trans-4- methylcyclohexyl)ethyl]-3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one(stereoisomer 1) 537 537 15.2  2

3-{4-(5-chloropyridin-3- yl)-2-[(R or S)-cyclo- propyl(ethoxy)methyl]-3-[(1R or S)-1- (trans-4- methylcyclohexyl)ethyl]- 3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one (stereoisomer 2) TFA 537 53715.3 13

3-{4-(5-chloropyridin-3- yl)-2-[(R or S)-cyclo- propyl(ethoxy)methyl]-3-[(1S or R)-1- (trans-4- methylcyclohexyl)ethyl]- 3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one (stereoisomer 3) TFA 537 53715.4  4

3-{4-(5-chloropyridin-3- yl)-2-[(S or R)-cyclo- propyl(ethoxy)methyl]-3-[(1S or R)-1- (trans-4- methylcyclohexyl)ethyl]- 3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one (stereoisomer 4) TFA 537 53715.5  4

3-{4-(5-chloropyridin-3- yl)-2-[(1S or R)-1- ethoxyethyl]-3-[(1R orS)-1-(trans-4- methylcyclohexyl)ethyl]- 3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one (stereoisomer 1) TFA 511 51115.6  5

3-{4-(5-chloropyridin-3- yl)-2-[(1R or S)-1- ethoxyethyl]-3-[(1R orS)-1-(trans-4- methylcyclohexyl)ethyl]- 3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one (stereoisomer 2) TFA 511 51115.7  5

3-{4-(5-chloropyridin-3- yl)-2-[(1R or S)-1- ethoxy-2-methoxyethyl]-3-[(1R or S)-1-(trans-4- methylcyclohexyl)ethyl]-3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one(stereoisomer 1) TFA 541 541 15.8  3

3-{4-(5-chloropyridin-3- yl)-2-[(1S or R)-1- ethoxy-2-methoxyethyl]-3-[(1R or S)-1-(trans-4- methylcyclohexyl)ethyl]-3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one (stereoisomer2) TFA 541 541

Example 16.13-{4-(5-chloropyridin-3-yl)-2-{(2R)-4-[(1-fluorocyclopropyl)carbonyl]-2-methylpiperazin-1-yl}-3-[(1RorS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one

Step 1: To a microwave vial were added (R)-tert-butyl3-methylpiperazine-1-carboxylate (purchased from Astatech) (155 mg,0.776 mmol), 2-bromo-4-(5-chloropyridin-3-yl)-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(faster eluting enantiomer 1 from Example 4.1/4.2, Step 3; 178 mg, 0.388mmol), cesium fluoride (177 mg, 1.164 mmol), DMSO (1 ml) and DIEA (0.203ml, 1.164 mmol). The reaction vial was capped and heated to 100° C.overnight. The reaction was then cooled to room temperature, dilutedwith EtOAc, washed with water and brine, dried over sodium sulfate,filtered, and concentrated. The residue was purified by columnchromatography on silica gel, eluting with EtOAc/hexanes to givetert-butyl (3R)-4-{4-(5-chloropyridin-3-yl)-6-cyano-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridin-2-yl}-3-methylpiperazine-1-carboxylate.MS ESI calc'd. for C₃₁H₄₀ClN₇O₂ [M+H]⁺ 578, found 578.

Step 2: Using a procedure analogous to that described in Example 2.1(Step 5), and starting with tert-butyl(3R)-4-{4-(5-chloropyridin-3-yl)-6-cyano-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridin-2-yl}-3-methylpiperazine-1-carboxylate,tert-butyl(3R)-4-{4-(5-chloropyridin-3-yl)-6-(N-hydroxycarbamimidoyl)-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridin-2-yl}-3-methylpiperazine-1-carboxylatewas prepared. MS ESI calc'd. for C₃₁H₄₃ClN₁₈O₃ [M+H]⁺ 611, found 611.

Step 3: Using a procedure analogous to that described in Example 2.1(Step 6), and starting with tert-butyl(3R)-4-{4-(5-chloropyridin-3-yl)-6-(N-hydroxycarbamimidoyl)-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridin-2-yl}-3-methylpiperazine-1-carboxylate,tert-butyl (3R)-4-[4-(5-chloropyridin-3-yl)-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-3-methylpiperazine-1-carboxylatewas prepared. MS ESI calc'd. for C₃₂H₄₁ClN₈O₄ [M+H]⁺ 637, found 637.

Step 4: A solution of HCl in 1,4-Dioxane (4.0 M, 0.718 ml, 2.9 mmol) wasadded to a stirred solution of tert-butyl(3R)-4-[4-(5-chloropyridin-3-yl)-3-[(1R or Sy1-(trans-4-methylcyclohexyl)ethyl]-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-3-methylpiperazine-1-carboxylate(61 mg, 0.096 mmol) in 1,4-dioxane (0.736 ml) at room temperature, andthe mixture was stirred at room temperature for 1.75 hr. The solvent wasevaporated under reduced pressure to give3-{4-(5-chloropyridin-3-yl)-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-2-[(2R)-2-methylpiperazin-1-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(HCl salt). MS ESI calc'd. for C₂₇H₃₃ClN₈O₂ [M+H]⁺ 537, found 537.

Step 5: 1-fluorocyclopropanecarboxylic acid (purchased from Wuxi AppTec)(25.4 mg, 0.244 mmol), N,N-diisopropylethylamine (63.1 mg, 0.488 mmol)and HATU (93.0 mg, 0.244 mmol) were added to a 0° C. solution of3-{4-(5-chloropyridin-3-yl)-3-[(1R orS)-1-(trans-4-methylcyclohexyl)ethyl]-2-[(2R)-2-methylpiperazin-1-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(HCl salt) (70.0 mg, 0.122 mmol) in DMF (1 ml), and the reaction waswarmed to room temperature and stirred for two hours. The reaction wasthen diluted with EtOAc, washed with water and brine, dried over sodiumsulfate, filtered, and concentrated. The residue was purified bypreparative HPLC (reverse phase, C-18), eluting withacetonitrile/water+0.1% TFA, to give3-{4-(5-chloropyridin-3-yl)-2-{(2R)-4-[(1-fluorocyclopropyl)carbonyl]-2-methylpiperazin-1-yl}-3-[(1RorS)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(TFA salt). MS ESI calc'd. for C₃₁H₃₆ClFN₈O₃ [M+H]⁺ 623, found 623. ¹HNMR (600 MHz, DMSO-d₆) δ 12.86 (s, 1H), 8.88 (s, 1H), 8.80 (d, J=2.2,1H), 8.40 (s, 1H), 8.10 (s, 1H), 4.06-3.39 (m, 5H), 3.00-2.83 (m, 1H),2.08-1.82 (m, 1H), 1.66-0.65 (m, 20H), 0.54-0.09 (m, 4H).

Example 16.1 was prepared as described above.

TABLE 16 FRET [M + H]+ [M + H]+ Ex. IC₅₀ (nM) Structure Chemical NameSalt Calc'd Obsv'd 16.1 1

3-{4-(5-chloropyridin-3- yl)-2-{(2R)-4-[(1- fluorocyclopropyl)carbonyl]-2-methylpiperazin-1-yl}- 3-[(1R or S)-1-(trans-4-methylcyclohexyl)ethyl]- 3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one (single enatiomer) 623 623

Preparative Example 17.1 (trans-4-ethylcyclohexyl)methanol

Borane in THF (1 M, 64.1 mL, 64.1 mmol) was added dropwise totrans-4-ethylcyclohexanecarboxylic acid (10.0 g, 64.1 mmol) in dry THF(100 mL) at −60° C. under a nitrogen atmosphere. The reaction wasallowed to warm to room temperature and stirred for 12 h. The reactionwas quenched with saturated ammonium chloride solution at 0° C., dilutedwith water (200 mL) and extracted with ethyl acetate (3×100 mL). Theorganic layer was washed with water (2×200 mL) and brine (100 mL), driedover anhydrous Na₂SO₄, filtered, and concentrated in vacuo to obtain(trans-4-ethylcyclohexyl)methanol. ¹H NMR (300 MHz, CDCl₃): δ 3.44 (d,J=6.0 Hz, 2H); 1.85-1.70 (dd, J=1.19, 10.5 Hz, 4H); 1.50-1.35 (m, 1H);1.30-1.10 (m, 4H); 0.95-0.85 (m, 6H).

Preparative Example 17.2 [trans-4-(trifluoromethyl)cyclohexyl]methanol

BH₃ (100 mL, 0.1 mol, 1.0 M solution in THF) was added dropwise to 0° C.solution of trans-4-(trifluoromethyl)cyclohexanecarboxylic acid (19.6 g,0.1 mol) in dry THF (100 mL). The reaction was stirred at roomtemperature for 5 h, quenched with water, extracted with EtOAc, washedwith brine, dried over Na₂SO₄, filtered, and concentrated to give[trans-4-(trifluoromethyl)cyclohexyl]methanol. ¹H NMR (300 MHz, CDCl₃):δ 3.48-3.47 (d, 2H), 2.00-1.89 (m, 5H), 1.51-1.43 (m, 1H), 1.35-1.26 (m,2H), 1.05-0.96 (m, 2H).

Preparative Example 17.3 (3-ethylcyclopentyl)methanol (mixture of cisand trans stereoisomers)

Step 1: To a stirred solution of 3-ethylcyclopentanone (4.00 g, 35.7mmol) in THF (70 mL) was added LDA (2 M in THF, 22.8 mL, 46.4 mmol) at−78° C., and the reaction was stirred at that temperature for 30minutes.1,1,1-trifluoro-N-phenyl-N—[(trifluoromethyl)sulfonyl]methanesulfonamide(14.0 g, 39.2 mmol) in THF (70 mL) was added at −78° C. The mixture wasallowed to warm to room temperature and stirred for 17 hours under anitrogen atmosphere. The reaction mixture was cooled to 0° C., slowlyquenched with aqueous ammonium chloride, and extracted with MTBE (3×30mL). The combined organic layers were washed with brine (2×30 mL), driedover anhydrous Na₂SO₄, filtered, and concentrated. Purification of theresidue on a silica gel column (10 to 100% EtOAc/hexanes) afforded3-ethylcyclopent-1-en-1-yl trifluoromethanesulfonate.

Step 2: To a stirred solution of 3-ethylcyclopent-1-en-1-yltrifluoromethanesulfonate (1.0 g, 4.08 mmol) in methanol (15 mL) and DMF(10 mL) were added Pd(OAc)₂ (45 mg, 0.20 mmol), DPPF (226 mg, 0.40mmol), and Et₃N (2.3 mL, 16.3 mmol), and the mixture was degassed withCO for 15 minutes. Then the reaction mixture was stirred at roomtemperature under a CO atmosphere (balloon) for 16 hours. Water wasadded to the reaction mixture, and it was extracted with MTBE (3×30 mL).The combined organic layers were washed with brine, dried over Na₂SO₄,and concentrated. Purification of the residue on a silica gel column (0to 100% EtOAc/hexanes) afforded methyl3-ethylcyclopent-1-enecarboxylate.

Step 3: To a stirred solution of methyl3-ethylcyclopent-1-enecarboxylate (1.60 g, 10.3 mmol) in methanol (15mL) was added 10% Pd/C (100 mg), and the mixture was purged withhydrogen for 10 minutes. Then reaction mixture was then stirred at roomtemperature for 16 hours under a hydrogen atmosphere (balloon). Thereaction mixture was then filtered through a pad of celite, and thefiltrate was concentrated to dryness to afford methyl3-ethylcyclopentanecarboxylate as a mixture of cis and trans isomers.

Step 4: To a stirred solution of methyl 3-ethylcyclopentanecarboxylate(1.50 g, 9.61 mmol) in THF (10 mL) was added LAH (1 M in THF; 9.6 mL,9.6 mmol) at 0° C., and the reaction mixture was stirred at 0° C. for 1hour. The reaction mixture was quenched with saturated Na₂SO₄, filteredthrough a pad of celite, washing with ethyl acetate, and the filtratewas concentrated to dryness to afford (3-ethylcyclopentyl)methanol(mixture of cis and trans isomers).

Example 17.13-{4-(5-chloropyridin-3-yl)-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[4-(trifluoromethyl)benzyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(racemic)

Step 1: 4,6-dichloro-3H-imidazo[4,5-c]pyridine (500 mg, 2.6 mmol), PPh₃(762 mg, 2.91 mmol) and THF (20 mL) were combined and stirred under anitrogen atmosphere. A solution of 4-trifluoromethyl benzyl alcohol (513mg, 2.91 mmol) in THF (5 mL) was added at rt. The reaction mixture wascooled to 0° C., and diisopropyl azodicarboxylate (587 mg, 2.91 mmol)was added dropwise. The reaction was warmed to rt and stirred overnightunder N₂. The reaction was then diluted with EtOAc, washed with brine,dried over Na₂SO₄, filtered, and concentrated. The crude residue wasdissolved in EtOAc (20 ml), p-toluenesulfonic acid (500 mg, 2.91 mmol)was added at rt, and the mixture was stirred for 3 h. The precipitatewhich formed was collected by filtration and rinsed with EtOAc. Thecollected precipitate was slurried in EtOAc (50 mL) and was stirredvigorously with aqueous sat'd NaHCO₃ (5 mL) for 30 min. The organiclayer was separated, and the aqueous layer was extracted several timeswith EtOAc. The combined organic layers were dried over Na₂SO₄,filtered, and concentrated. The crude product was purified by silica gelchromatograhy with 20% to 100% EtOAc/hexanes to obtain the desiredisomer,4,6-dichloro-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine. ¹HNMR (400 MHz, CDCl₃): δ8.85 (s, 1H); 7.96 (s, 1H); 7.71 (d, J=8.0 Hz,2H), 7.33 (d, J=8.0 Hz, 2H), 5.89 (s, 2H). MS APCl calc'd. forC₁₄H₈Cl₂F₃N₃ [M+H]⁺ 346, found 346.

Step 2: N-bromosuccinimide (352 mg, 1.98 mmol) was added to a solutionof 4,6-dichloro-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine(200 mg, 0.99 mmol) stirring in degassed chloroform (20 mL) at roomtemperature. The reaction was heated to reflux for 1 hour. The mixturewas cooled to room temperature, diluted with dichloromethane, and washedwith saturated aqueous sodium thiosulfate and brine. The organic layerwas dried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by silica gel chromatography (0-100%ethyl acetate/hexanes, linear gradient) to afford2-bromo-4,6-dichloro-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine.MS APCl calc'd. for C₁₄H₇BrCl₂F₃N₃ [M+H]⁺ 426, found 426.

Step 3: To a vial were added2-bromo-4,6-dichloro-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine(200 mg, 0.47 mmol), octahydrocyclopenta[b][1,4]oxazine hydrochloride(purchased from Enamine); 147 mg, 0.9 mmol), potassium fluoride (81 mg,1.41 mmol), DIEA (246 μL, 1.41 mmol), and DMSO (2 mL). The vial wassealed and heated to 90° C. for 1 hour. The reaction mixture was cooledto room temperature, diluted with ethyl acetate, and washed with waterand brine. The organic layer was dried over sodium sulfate, filtered,and concentrated under reduced pressure. The residue was purified bysilica gel chromatography (0-60% ethyl acetate/hexanes, linear gradient)to afford4,6-dichloro-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-344-(trifluoromethyl)benzyl]-3H-imidazo[4,5-c]pyridine(racemate). MS APCl calc'd. for C₂₁H₁₉O₂F₃N₄O [M+H]⁺ 471, found 471.

Step 4:4,6-dichloro-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[4-(trifluoromethyl)benzyl]-3H-imidazo[4,5-c]pyridine(racemate, 180 mg, 0.38 mmol), 5-chloropyridine-3-boronic acid (65.7 mg,0.42 mmol), cesium carbonate (617 mg, 1.9 mmol), and1,1′-Bis(diphenylphosphino) ferrocene-palladium(II)dichloride (46.3 mg,0.076 mmol) were combined in a vial that had been oven-dried and flushedwith nitrogen. Dioxane (75 mL) was added, and the vial was sealed andheated to 90° C. for 4 hours. The reaction mixture was cooled to roomtemperature, filtered through celite, and the filtrate was concentratedunder reduced pressure. The residue was purified by silica gelchromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford6-chloro-4-(5-chloropyridin-3-yl)-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[4-(trifluoromethyl)benzyl]-3H-imidazo[4,5-c]pyridine(racemic). MS APCl calc'd. for C₂₆H₂₂Cl₂F₃N₅O [M+H]⁺ 548, found 548.

Step 5: Palladium(II) acetate (70 mg, 0.312 mmol) and(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (195 mg, 0.313 mmol)were placed in a dry flask. N,N-dimethylacetamide (18.7 mL) was addedand the mixture was degassed for three minutes with nitrogen. Sulfuricacid (0.015 mL) was added, and the mixture was degassed for anadditional three minutes with nitrogen. The flask was sealed and heatedto 80° C. for 30 minutes. The mixture was cooled to room temperature andadded to a separate nitrogen purged flask containing6-chloro-4-(5-chloropyridin-3-yl)-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[4-(trifluoromethyl)benzyl]-3H-imidazo[4,5-c]pyridine(racemic; 0.5 g, 0.9 mmol), zinc cyanide (46 mg, 0.45 mmol), and zinc (6mg, 0.09 mmol). The flask was purged with nitrogen for five minutes,sealed, and heated to 100° C. for 2 hrs. The reaction mixture was cooledto room temperature, filtered, diluted with ethyl acetate, and washedwith water and brine. The organic layer was dried over sodium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (0-100% ethyl acetate/hexanes,linear gradient) to afford4-(5-chloropyridin-3-yl)-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[4-(trifluoromethyl)benzyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(racemic). MS APCl calc'd. for C₂₇H₂₂ClF₃N₆O [M+H]⁺ 539, found 539.

Steps 6 and 7: Using a procedure analagous to that described in Example2.1 (Steps 5 and 6) and starting with4-(5-chloropyridin-3-yl)-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[4-(trifluoromethyl)benzyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(racemic),3-{4-(5-chloropyridin-3-yl)-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[4-(trifluoromethyl)benzyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(racemic) was prepared. ¹H NMR (500 MHz, CD₃OD) δ 8.59 (s, 1H), 8.51 (s,1H), 8.23 (s, 1H), 7.65 (d, J=6.0 Hz, 1H), 7.35 (d, J=8.4, 2H), 6.43 (d,J=8.0 Hz, 2H), 5.55 (d, J=17.2 Hz, 1H), 4.82 (d, J=17.2 Hz, 1H),3.92-4.00 (m, 2H), 3.46-3.51 (m, 2H), 3.10-3.25 (m, 1H), 3.05-3.10 (m,1H), 1.24-1.32 (m, 4H), 0.86-0.91 (m, 2H). MS APCl calc'd. forC₂₈H₂₃ClF₃N₇O₃ [M+H]⁺ 598, found 598.

The examples in Table 17 (other than Example 17.1) were prepared usingprocedures similar to those described above.

TABLE 17 FRET IC₅₀ [M + H]+ [M + H]+ Ex. (nM) Structure Chemical NameSalt Calc'd Obsv'd 17.1  39

3-{4-(5-chloropyridin- 3-yl)-2-[(trans)- hexahydrocyclopenta[b][1,4]oxazin-4-(4aH)- yl]-3-[4- (trifluoromethyl)benzyl]-3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one (racemic) 598598 17.2  5

3-{4-(5-chloropyridin- 3-yl)-3-[(trans-4- ethylcyclohexyl)methyl]-2-[(trans)- hexahydrocyclopenta[b] [1,4]oxazin-4(4aH)-yl]-3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one (racemic)564 564 17.3  25

5-{4-(5-chloropyridin- 3-yl)-3-[(trans-4- ethylcyclohexyl)methyl]-2-[(trans)-hexahydro- cyclopenta[b][1,4]oxazin- 4(4aH)-yl]-3H-imidazo[4,5-c]pyridin-6-yl}- 1,3,4-oxadiazol-2(3H)- one(racemic) 564 564 17.4244

3-{4-(5-chloropyridin- 3-yl)-3-[3-fluoro-4- (trifluoromethyl)benzyl]-2-[(trans)- hexahydrocyclopenta [b][1,4]oxazin-4(4aH)-yl]-3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one(enantiomer 1) 616 616 17.5  28

3-{4-(5-chloropyridin- 3-yl)-3-[3-fluoro-4- (trifluoromethyl)benzyl]-2-[(trans)- hexahydrocyclopenta [b][1,4]oxazin-4(4aH)-yl]-3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one(enantiomer 2) 616 616 17.6  38

3-[4-(5-chloropyridin- 3-yl)-2-[(trans)- hexahydrocyclopenta[b][1,4]oxazin-4(4aH)- yl]-3-{[trans-4- (trifluoromethyl)cyclohexyl]methyl}-3H- imidazo[4,5-c]pyridin- 6-yl]-1,2,4-oxadiazol-5(4H)-one (racemic) 604 604 17.7  16

3-{4-(5-chloropyridin- 3-yl)-3-[(3-ethyl- cyclopentyl)methyl]-2-[(4aR,7aR)- hexahydrocyclopenta [b][1,4]oxazin-4-(4aH)-yl]-3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one (mixtureof diastereomers) 550 550

Preparative Example 18.14,6-dichloro-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine(racemic)

Using a procedure analagous to that described in Example 2.1 (Steps 1and 2) and starting with4,6-dichloro-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine(Preparative Example 2.3) and(trans)-octahydrocyclopenta[b][1,4]oxazine.HCl (purchased from Enamine),4,6-dichloro-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine(racemic) was prepared.

Preparative Example 18.2 3-(tributylstannanyl)pyridazine

In a sealable tube were placed 3-bromopyridazine (1.0 g, 6.28 mmol) andhexabutyldistannane (3.6 mL, 6.28 mmol). 1,4-dioxane (4 mL) was added,and the reaction mixture was purged with nitrogen for five minutes.Pd(dppf)Cl₂.CH₂Cl₂ (153 mg, 0.018 mmol) was added, and the mixture wasdegassed with nitrogen again for 5 minutes. The tube was sealed andheated to 100° C. for 16 hours. The reaction mixture was cooled to roomtemperature, filtered through celite, washing with ethyl acetate, andthe filtrate was concentrated under reduced pressure. The residue waspurified by column chromatography with 10% EtOAc/petroleum ethercontaining 0.1% Et₃N to afford 3-(tributylstannyl)pyridazine. MS ES/APClcalc'd. for C₁₆H₃₀N₂Sn [M+H]⁺ 371, found 371. ¹H NMR (400 MHz, CDCl₃): δ8.72 (dd, J=1.5, 2.4 Hz, 1H), 8.56 (d, J=1.7 Hz, 1H), 8.37 (d, J=2.6 Hz,1H), 1.62-1.53 (m, 8H), 1.39-1.33 (m, 6H), 1.31-1.19 (m, 5H), 0.95-0.90(m, 8H).

Example 18.13-{4-[5-chloro-2-(dimethylamino)pyridin-3-yl]-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(racemic)

Step 1:4,6-dichloro-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine(racemic, 422 mg, 1 mmol),5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(340 mg, 2 mmol) and Cs₂CO₃ (980 mg, 3 mmol) were added to degasseddioxane:water (10 mL: 2 mL), followed by the addition of[1,1′-bis(di-tert-butylphosphino)ferrocene]PdCl₂ (130 mg, 0.2 mmol). Thereaction was heated at 90° C. for 24 hours. Water and EtOAc were added.The aqueous layer was extracted with EtOAc several times. The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified on a silica gel column(0 to 60% EtOAc/hexanes) to afford6-chloro-4-(5-chloro-2-fluoropyridin-3-yl)-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine(racemic). MS ES calc'd. for C₂₆H₃₀Cl₂FN₅O [M+H]⁺ 518, found 518.

Step 2: To a solution of dimethylamine hydrochloride (580 mg, 7.25 mmol)and sodium bicarbonate (812 mg, 9.67 mmol) in EtOH:water (4 mL:2 mL) wasadded6-chloro-4-(5-chloro-2-fluoropyridin-3-yl)-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine(racemic) (125 mg, 0.24 mmol). The reaction was heated to 90° C. for 5hours. The reaction was then concentrated and diluted with EtOAc. Theorganic layer was washed with water and brine, dried over sodiumsulfate, filtered, and concentrated. Purification of the residue on asilica gel column (0 to 45% EtOAc/hexanes) afforded5-chloro-3-{6-chloro-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-4-yl}-N,N-dimethylpyridin-2-amine(racemic). MS ES calc'd. for C₂₈H₃₆Cl₂N₆O [M+H]⁺ 543, found 543.

Step 3: A vial was charged with H₂SO₄ (6 mg, 0.005 mmol) and DMA (3 mL)and was degassed with N₂ for 3 minutes. Pd(OAc)₂ (13.5 mg, 0.005 mmol)and dppf (33.4 mg, 0.005 mmol) were added. The vial was sealed andheated at 80° C. for 30 minutes and then was cooled to room temperature.1 mL of this solution was added to a second vial containing5-chloro-3-{6-chloro-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-4-yl}-N,N-dimethylpyridin-2-amine(racemic, 81 mg, 0.14 mmol), Zn(CN)₂ (7.8 mg, 0.06 mmol) and Zn (1.0 mg,0.014 mmol) under an atmosphere of N₂. The reaction was sealed andheated at 95° C. for 18 hours. Water (5 mL) was added, and the aqueouslayer was extracted with EtOAc (2×5 mL). The combined organic layerswere dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.The residue was purified on a silica gel column (0 to 50% EtOAc/hexanes)to afford4-[5-chloro-2-(dimethylamino)pyridin-3-yl]-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(racemic). MS ES calc'd. for C₂₉H₃₆ClN₇O [M+H]⁺ 534, found 534.

Step 4: Hydroxylamine hydrochloride (4.3 mg, 0.07 mmol) and sodiumbicarbonate (7 mg, 0.08 mmol) were dissolved in water (0.4 mL) andstirred at room temperature for 10 minutes, allowing gas to evolve. Thissolution was then added to a solution of4-[5-chloro-2-(dimethylamino)pyridin-3-yl]-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile(racemic, 26 mg, 0.05 mmol) in ethanol (0.2 mL). This reaction mixturewas stirred at 90° C. for 1 hour. The reaction mixture was concentratedand diluted with water (2 mL). The solid was filtered off to afford(crude)4-[5-chloro-2-(dimethylamino)pyridin-3-yl]-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-N-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide(racemic). MS ES calc'd. for C₂₉H₃₉ClN₈O₂ [M+H]⁺ 567, found 567.

Step 5: To a solution of4-[5-chloro-2-(dimethylamino)pyridin-3-yl]-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-N-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide(racemic, 22 mg, 0.075 mmol) and 1,1′-carbonyldiimidazole (12 mg, 0.07mmol) in acetonitrile (1 mL) was added 1,8-diazabicycloundec-7-ene (23mg, 0.15 mmol). The reaction was stirred at room temperature for 18hours. The reaction was then diluted with CH₂Cl₂ and washed with water.The organic layer was dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified on a silica gel column (0 to 10% MeOH/CH₂Cl₂) toafford3-{4-[5-chloro-2-(dimethylamino)pyridin-3-yl]-2-Rtrans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(racemic). NMR shows 8:2 mixture of rotamers, ¹H NMR (400 MHz, CD₃OD)(for major rotamer) δ 8.27 (d, J=2.8 Hz, 1H), 8.12 (s, 1H), 7.98 (d,J=2.8 Hz, 1H), 3.76-4.04 (m, 3H), 3.35-3.51 (m, 3H), 3.13 (m, 1H), 2.98(m, 1H), 2.53 (s, 6H), 2.34 (m, 1H), 1.64-1.77 (m, 3H), 1.44-1.56 (m,3H), 1.12-1.24 (m, 3H), 0.71-0.84 (m, 7H), 0.50-0.62 (m, 2H). MS EScalc'd. for C₃₀H₃₇ClN₈O₃ [M+H]⁺ 593, found 593

Example 18.43-{4-[5-chloro-2-(2-hydroxyethoxy)pyridin-3-yl]-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(racemic)

Step 1: NaH (24 mg, 0.6 mmol) was added to solution of2-((tert-butyldimethylsilyl)oxy)ethanol (70 mg, 0.4 mmol) in DMF (1.0mL) at 0° C., and the reaction was stirred at 0° C. for 30 minutes. Asolution of6-chloro-4-(5-chloro-2-fluoropyridin-3-yl)-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine(racemic, Example 18.1, Step 1; 100 mg, 0.2 mmol) was added, and thereaction was stirred at 0° C. for 30 minutes. The reaction was quenchedby adding saturated aqueous NH₄Cl solution and extracted using EtOAc.The organic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated. Purification of the residue on a silica gel column with 0to 50% EtOAc/hexane afforded4-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)-5-chloropyridin-3-yl]-6-chloro-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine(racemic). MS APCl calc'd. for C₃₄H₄₉Cl₂N₅O₃Si [M+H]⁺ 674, found 674.

Steps 2-4: Following procedures similar to those descrbed in Example18.1 (Steps 3-5), and starting with4-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)-5-chloropyridin-3-yl]-6-chloro-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine(racemic),3-{-4-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)-5-chloropyridin-3-yl]-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(racemic) was prepared.

Step 5: TBAF (0.1 mL, 1 M in THF, 0.1 mmol) was added to solution of3-{4-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)-5-chloropyridin-3-yl]-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(racemic, 20 mg, 0.027 mmol) in THF (1.0 mL) at room temperature andstirred for 16 hours. The reaction was concentrated, and the residue wasdissolved in CH₂Cl₂/IPA (4:1, 15 mL) and washed twice using water (10mL). The layers were separated, and the organic layer was concentratedunder reduced pressure. Purification of the residue on a silica gelcolumn with 0 to 10% MeOH/CH₂Cl₂ afforded3-{4-[5-chloro-2-(2-hydroxyethoxy)pyridin-3-yl]-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(racemic). ¹H NMR (400 MHz, CDCl₃) δ 8.28 (br s, 2H), 7.26 (s, 1H), 4.70(d, J=10.2 Hz, 1H), 3.90 (t, J=12.2 Hz, 2H), 3.70-3.80 (m, 3H),3.45-3.74 (m, 2H), 3.17-3.32 (m, 2H), 3.10 (t, J=12.4 Hz, 2H), 2.39 (m,1H), 1.99 (m, 1H), 1.88 (m, 1H), 1.66-1.76 (m, 2H), 1.45-1.62 (m, 6H),1.02-1.32 (m, 2H), 0.88 (m, 1H), 0.77 (d, J=7.4 Hz, 3H), 0.42-0.60 (m,2H). MS ES calc'd. for C₃₀H₃₆ClN₇O₅ [M−1]⁻ 608, found 608.

Example 18.95-chloro-3-{2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-4-yl}pyridin-2(1H)-one

Step 1:4,6-dichloro-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine(racemic, 460 mg, 1.08 mmol),(2-(benzyloxy)-5-chloropyridin-3-yl)boronic acid (purchased fromCombi-Blocks Inc.; 372 mg, 1.41 mmol) and 2M aqueous Na₂CO₃ (5 mL, 10mmol) were added to degassed 1,2-dimethoxyethane (15 mL), followed bythe addition of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (159 mg, 0.2mmol). The reaction was heated at 90° C. for 6 hours. Water and EtOAcwere added. The aqueous layer was extracted several times with EtOAc.The combined organic layers were dried over anhydrous Na₂SO₄, filtered,and concentrated in vacuo. The residue was purified on a silica gelcolumn (0 to 30% EtOAc/hexanes) to afford4-[2-(benzyloxy)-5-chloropyridin-3-yl]-6-chloro-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine(racemic). MS ES calc'd. for C₃₃H₃₇Cl₂N₅O₂ [M+H]⁺ 606, found 606.

Step 2:4-[2-(benzyloxy)-5-chloropyridin-3-yl]-6-chloro-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine(racemic, 450 mg, 0.74 mmol), zinc cyanide (43 mg, 0.37 mmol) andPd(PPh₃)₄ (128 mg, 0.11 mmol) were placed in a dry vial. Degassed DMA (4mL) was added to the reaction, and the reaction was placed under anatmosphere of Ar, sealed, and heated at 90° C. for 12 hours. Thereaction was then cooled to room temperature, and cold water was addedslowly. The aqueous layer was extracted with EtOAc. The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated under reducedpressure. Purification of the residue on a silica gel column (0 to 50%EtOAc/hexanes) afforded4-[2-(benzyloxy)-5-chloropyridin-3-yl]-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrileas a racemic mixture. The enantiomers were separated on a chiral ODcolumn using 2% IPA/98% heptanes. MS ES calc'd. for C₃₄H₃₇ClN₆O₂ [M+H]⁺597, found 597.

Steps 3 and 4: Starting with the faster eluting enantiomer of4-[2-(benzyloxy)-5-chloropyridin-3-yl]-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile,3-{4-[2-(benzyloxy)-5-chloropyridin-3-yl]-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-onewas prepared using procedures similar to those described in Example 18.1(Steps 4 and 5)

Step 5: To a solution of3-{4-[2-(benzyloxy)-5-chloropyridin-3-yl]-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(23 mg, 0.03 mmol) in anhydrous CH₂Cl₂ at 0° C., Et₃SiH (0.029 mL, 0.18mmol) and PdCl₂ (2 mg, 0.01 mmol) were added. The reaction was stirredat 0° C. for 0.5 hour and then concentrated. The residue was purified ona C-18 column eluting with 40% water/60% acetonitrile to afford5-chloro-3-{2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-4-yl}pyridin-2(1H)-one.¹H NMR (400 MHz, CD₃OD) δ 8.09 (s, 1H), 8.04 (br s, 1H), 7.76 (d, J=2.8Hz, 1H), 4.01 (m, 1H), 3.83-3.93 (m, 3H), 3.62 (m, 1H), 3.54 (m, 1H),3.38 (m, 1H), 3.12 (m, 1H), 2.96 (m, 1H), 2.28 (m, 1H), 1.97 (m, 1H),1.49-1.82 (m, 6H), 1.19-1.25 (m, 2H), 0.91-1.00 (m, 2H), 0.78 (d, J=6.4Hz, 3H), 0.57-0.74 (m, 3H). MS ES calc'd. for C₂₈H₃₂ClN₇O₄ [M+H]⁺ 566,found 566.

Example 18.153-{3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-4-(pyrazin-2-yl)-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one

Step 1: In a sealable tube were placed4,6-dichloro-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine(Example 2.1, Step 2; 700 mg, 1.52 mmol), 4-(tributylstannyl)pyridazine(619 mg, 1.67 mmol), and Pd(dppf)Cl₂, dichlormethane complex (68 mg,0.084 mmol). Dioxane (8 mL) that had been purged with nitrogen wasadded. The tube was sealed and heated to 100° C. for 16 hours. Thereaction mixture was cooled to room temperature, filtered throughcelite, and the filtrate was concentrated under reduced pressure. Theresidue was purified on a silica gel column using 25-40% ethylacetate/petroleum ether as eluent to afford6-chloro-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-4-(pyrazin-2-yl)-3H-imidazo[4,5-c]pyridine.MS ES/APCl calc'd. for C₂₈H₃₁ClN₆O [M+H]⁺ 503, found 503.

Step 2: To a sealable tube were added6-chloro-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-4-(pyrazin-2-yl)-3H-imidazo[4,5-c]pyridine(250 mg, 0.497 mmol) and Zn(CN)₂ (46 mg, 0.397 mmol). DMF (4 mL) wasadded, and the mixture was purged with nitrogen for 5 minutes.Pd(dppf)Cl₂ dichloromethane complex (20.2 mg, 0.024 mmol) was added, andthe mixture was degassed with nitrogen again for 5 minutes. The tube wassealed and heated to 140° C. for 2.5 hours. The reaction mixture wascooled to room temperature, filtered, diluted with ethyl acetate, andwashed with water and brine. The organic layer was dried over anhydroussodium sulfate, filtered, and concentrated under reduced pressure. Theresidue was purified on a silica gel column using 30-45% ethylacetate/petroleum ether as eluent to afford3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-4-(pyrazin-2-yl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ES/APCl calc'd. for C₂₉H₃₁N₇O [M+H]⁺ 494, found 494.

Steps 3 and 4: Using procedures analagous to those described in Example2.1 (Steps 5 and 6),3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-4-(pyrazin-2-yl)-3H-imidazo[4,5-c]pyridine-6-carbonitrilewas converted to3-{3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-4-(pyrazin-2-yl)-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one.MS ES/APCl calc'd. for C₃₀H₃₂N₈O₃ [M+H]⁺ 553, found 553. ¹H NMR (400MHz, DMSO-d₆): δ 12.91 (s, 1H), 9.73 (s, 1H), 9.46 (d, J=5.2 Hz, 1H),8.10 (dd, J=2.0, 5.4 Hz, 1H), 7.97 (s, 1H), 7.48 (d, J=7.2 Hz, 2H),7.31-7.21 (m, 3H), 4.95-4.90 (m, 1H), 4.07-3.82 (m, 5H), 3.67-3.56 (m,2H), 3.40-3.30 (m, 1H), 1.40-1.30 (m, 2H), 1.10-1.00 (m, 1H), 0.77-0.42(m, 8H), 0.37-0.34 (m, 2H).

The examples in Table 18 (other than Examples 18.1, 18.4, 18.9, and18.15) were prepared using procedures similar to those described above.In some cases, enantiomers were separated using chiral columns andstandard separation techniques.

TABLE 18 FRET IC₅₀ [M + H]+ [M + H]+ Ex. (nM) Structure Chemical NameSalt Calc'd Obsv'd 18.1  2

3-{4-[5-chloro-2- (dimethylamino) pyridin-3-yl]-2- [(trans)-hexa-hydrocyclopenta [b][1,4]oxazin- 4(4aH)-yl]-3-[(trans-4-methylcyclohexyl) methyl]-3H- imidazo[4,5-c] pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (racemic) 593 593 18.2  33

3-{4-(5-chloro-2- methylpyridin-3-yl)- 2-[(4aS,7aS)- hexahydrocyclopenta[b][1,4]oxazin- 4(4aH)-yl]-3-[(trans- 4-methylcyclohexyl) methy]-3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one 564 564 18.3  1

3-{4-(5-chloro-2- methylpyridin-3-yl)- 2-[(4aR,7aR)- hexahydrocyclopenta[b][1,4]oxazin- 4(4aH)-yl]-3-[(trans- 4-methylcyclohexyl)methyl]-3H-imidazo [4,5-c]pyridin-6-yl}- 1,2,4-oxadiazol- 5(4H)-one 564564 18.4  1

3-{4-[5-chloro-2-(2- hydroxyethoxy) pyridin-3-yl]-2- [(trans)-hexahydro-cyclopenta[b][1,4] oxazin-4(4aH)-yl]- 3-[(trans-4- methylcyclohexyl)methyl]-3H- imidazo[4,5-c] pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one(racemic) 608 (M − 1) 608 (M − 1) 18.5  24

3-{4-(5-chloro-2- methoxypyridin-3- yl)-2-[(4aS,7aS)-hexahydrocyclopenta [b][1,4]oxazin- 4(4aH)-yl]-3-[(trans-4-methylcyclohexyl) methyl]-3H-imidazo [4,5-c]pyridin-6-yl}-1,2,4-oxadiazol- 5(4H)-one 580 580 18.6  1

3-{4-(5-chloro-2- methoxypyridin-3- yl)-2-[(4aR,7aR)-hexahydrocyclopenta [b][1,4]oxazin- 4(4aH)-yl]-3-[(trans-4-methylcyclohexyl) methyl]-3H- imidazo[4,5-c] pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one 580 580 18.7  1

3-{4-[5-chloro-2-(2- methoxyethoxy) pyridin-3-yl]-2- [(4aR,7aR)-hexahydrocyclopenta [b][1,4]oxazin- 4(4aH)-yl]-3-[(trans-4-methylcyclohexyl) methyl]-3H- imidazo[4,5-c] pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one 624 624 18.8  21

3-{4-[5-chloro-2-(2- methoxyethoxy) pyridin-3-yl]-2- [(4aS,7aS)-hexahydrocyclopenta [b][1,4]oxazin- 4(4aH)-yl]-3-[(trans-4-methylcyclohexyl) methyl]-3H- imidazo[4,5-c]pyridin- 6-yl}-1,2,4-oxadiazol-5(4H)-one 624 624 18.9  2

5-chloro-3-{2- [(4aR,7aR)- hexahydrocyclopenta [b][1,4]oxazin-4(4aH)-yl]-3-[(trans- 4-methylcyclohexyl) methyl]-6-(5-oxo-4,5-dihydro-1,2,4- oxadiazol-3-yl)-3H- imidazo[4,5-c] pyridin-4-yl}pyridin-2(1H)-one 566 566 18.10  2

3-{2-[(4aR,7aR)- hexahydrocyclopenta [b][1,4]oxazin-4(4aH)-yl]-3-[(trans- 4-methylcyclohexyl) methyl]-4-(5-methylpyridin-3-yl)- 3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one 528 (M − 1) 528 (M − 1) 18.11 210

3-{2-[(4aS,7aS)-hexa- hydrocyclopenta[b] [1,4]oxazin-4(4aH)-yl]-3-[(trans-4- methylcyclohexyl) methyl]-4-(5- methylpyridin-3-yl)-3H-imidazo[4,5-c] pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one 528 (M − 1)528 (M − 1) 18.12  2

3-{4-[5-chloro-2- (methylamino)pyridin- 3-yl]-2-[(trans)-hexahydrocyclopenta [b][1,4]oxazin- 4(4aH)-yl]-3-[(trans-4-methylcyclohexyl) methyl]-3H- imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (racemic) 579 579 18.13  1

5-chloro-3-{3-[(trans- 4-methylcyclohexyl) methyl]-6-(5-oxo-4,5-dihydro-1,2,4- oxadiazol-3-yl)-2- [(3R)-3- phenylmorpholin-4-yl]-3H-imidazo[4,5- c]pyridin-4- yl}pyridin-2(1H)-one 602 602 18.14  65

3-{3-[(trans-4- methylcyclohexyl) methyl]-2-[(3R)-3- phenylmorpholin-4-yl]-4-pyrimidin-5-yl- 3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one 553 553 18.15 119

3-{3-[(trans-4- methylcyclohexyl) methyl]-2-[(3R)-3- phenylmorpholin-4-yl]-4-(pyrazin-2-yl)- 3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one TFA 553 553 18.16  72

3-{3-[(trans-4- methylcyclohexyl) methyl]-2-[(3R)-3- phenylmorpholin-4-yl]-4-(pyridazin-4-yl)- 3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one TFA 553 553 18.17 112

3-{3-[(trans-4- methylcyclohexyl) methyl]-2-[(3R)-3- phenylmorpholin-4-yl]-4-(pyridazin-3-yl)- 3H-imidazo[4,5- c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one TFA 553 553

Example 19.13-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[1-methyl-2-(methylsulfanyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(racemate)

3-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(1-methylethenyl)-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one(synthesized in a manner similar to Example 9.1; 100 mg, 0.22 mmol) wastaken up in MeOH (1.5 mL) at room temperature, and sodium thiomethoxide(376 mg, 5.4 mmol) was added. The reaction was sealed and heated at 65°C. for 2 hours. The reaction was then quenched with saturated ammoniumchloride and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous MgSO₄, filtered, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (0 to 100% EtOAc/hexanes) to afford3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[1-methyl-2-(methylsulfanyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(racemate). ¹H NMR (300 MHz, CDCl₃) δ 8.69-8.74 (m, 1H), 8.57-8.62 (m,1H), 8.43 (s, 1H), 7.89-7.94 (m, 1H), 3.71-3.93 (m, 2H), 3.22-3.38 (m,1H), 3.06-3.19 (m, 1H), 2.88-2.99 (m, 1H), 2.07 (s, 3H), 1.48-1.59 (m,1H), 1.53 (d, J=6.7 Hz, 3H), 1.22-1.38 (m, 2H), 1.08-1.21 (m, 1H),0.85-1.07 (m, 3H), 0.78 (d, J=6.4 Hz, 3H), 0.66-0.75 (m, 1H), 0.47-0.66(m, 2H); MS ES calc'd. for C₂₅H₂₉ClN₆O₂S [M+H]⁺ 513, found 513.

Example 19.23-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[1-methyl-2-(methylsulfonyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(racemate)

To3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[1-methyl-2-(methylsulfanyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(Example 19.1, 10 mg, 0.02 mmol) in dichloromethane (1.0 mL) was addedm-CPBA (10 mg, 0.06 mmol) at 0° C., and the reaction mixture was stirredfor 1 hour at 0° C. and then for 14 hours at room temperature under anitrogen atmosphere. The reaction was quenched with aqueous saturatedNaHCO₃ solution (2 mL) and extracted with ethyl acetate (3×10 mL). Thecombined organic extracts were washed with brine (5 mL), dried overanhydrous Na₂SO₄, filtered, and concentrated. Purification of theresidue by C-18 reverse phase chromatography (0 to 100% CH₃CN/H₂O)afforded3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[1-methyl-2-(methylsulfonyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(racemate). ¹H NMR (300 MHz, CD₃OD) δ 8.72-8.85 (m, 2H), 8.24-8.35 (m,2H), 3.81-4.17 (m, 4H), 3.48-3.79 (m, 1H), 2.98 (s, 3H), 1.99-2.14 (m,1H), 1.46-1.65 (m, 1H), 1.59 (d, J=6.7 Hz, 3H), 1.02-1.37 (m, 3H),0.82-1.02 (m, 3H), 0.78 (d, J=6.7 Hz, 3H), 0.44-0.68 (m, 2H); MS EScalc'd. for C₂₅H₂₉ClN₆O₄S [M+H]⁺ 545, found 545.

Example 19.53-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-{2-methyl-1-[(methylsulfonyl)methyl]propyl}-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one(racemic)

To a stirred solution of3-{4-(5-chloropyridin-3-yl)-2-(3-methylbut-1-en-2-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(synthesized in a manner similar to Example 9.1; 20 mg, 0.046 mmol) indry ethanol (0.7 mL) was added sodium methanesulfinate (47 mg, 0.46mmol) followed by acetic acid (27 μL, 0.046 mmol). The reaction mixturewas heated to 60° C. for 12 h. The reaction mixture was then cooled toroom temperature and concentrated under reduced pressure. The residuewas dissolved in ethyl acetate and washed with water and brine. Theorganic layer was dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue obtained was purifiedby reverse phase prep-HPLC (Kromasil C18, water/MeOH+0.1% TFA) to give3-[4-(5-chloropyridin-3-yl)-3-(trans-4-methylcyclohexyl)methyl]-2-{2-methyl-1-[(methylsulfonyl)methyl]propyl}-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one(TFA salt, racemate). ¹H NMR (400 MHz, DMSO-d₆): δ 12.90 (br s, 1H),8.86 (s, 1H), 8.85 (s, 1H), δ 8.43 (s, 1H), 8.24 (s, 1H), 4.07-3.96 (m,2H), 3.84-3.79 (m, 1H), 3.67-3.64 (m, 2H), 3.02 (s, 3H), 2.21-2.16 (m,1H), 1.39 (d, J=11.6 Hz, 2H), 1.22-1.15 (m, 2H), 1.04 (d, J=6.7 Hz, 3H),0.83 (d, J=6.7 Hz, 3H), 0.70 (d, J=6.5 Hz, 3H), 0.78-0.41 (m, 6H). MSES/APCl calc'd. for C₂₇H₃₃ClN₆O₄S [M+H]⁺ 573, found 573.

The examples in Table 19 (other than Examples 19.1, 19.2, and 19.5) wereprepared using procedures similar to those described above.

TABLE 19 FRET [M + H]+ [M + H]+ Ex. IC₅₀ (nM) Structure Chemical NameSalt Calc'd Obsv'd 19.1  7

3-{4-(5-chloropyridin- 3-yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-[1-methyl-2- (methylsulfanyl)ethyl]- 3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one (racemate) 513 513 19.2 37

3-{4-(5-chloropyridin- 3-yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-[1-methyl-2- (methylsulfonyl)ethyl]- 3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one (racemate) 545 545 19.3  2

3-[4-(5-chloropyridin- 3-yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-{1- [(methylsulfanyl) methyl]propyl}-3H-imidazo[4,5-c]pyridin- 6-yl]-1,2,4-oxadiazol- 5(4H)-one (racemate) 527527 19.4  7

3-[4-(5-chloropyridin- 3-yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-{1- [(methylsulfonyl) methyl]propyl}-3H-imidazo[4,5-c]pyridin- 6-yl]-1,2,4-oxadiazol- 5(4H)-one (racemate) 559559 19.5  5

3-[4-(5-chloropyridin- 3-yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-{2-methyl-1- [(methylsulfonyl)methyl] propyl}-3H-imidazo[4,5-c]pyridin- 6-yl]-1,2,4-oxadiazol- 5(4H)-one (racemic) TFA573 573

Example 20.16-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}pyridin-2(1H)-one

Step 1: A mixture of6-chloro-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine(Example 2.1, Step 3; 130 mg, 0.242 mmol),2-methoxy-6-(tri-n-butylstannyl)pyridine (122 mg, 0.308 mmol), andPd(PPh₃)₄ (28.0 mg, 0.0242 mmol) in DMF (2.9 mL) was degassed and heatedat 100° C. for 16 hours under a nitrogen atmosphere. The reactionmixture was cooled to room temperature and diluted with water (10 mL).The reaction mixture was extracted with ethyl acetate (3×10 mL). Thecombined organic layers were washed with saturated aqueous KF solution(10 mL), water (2×10 mL) and brine (10 mL). The organic layer was driedover anhydrous Na₂SO₄, filtered, and concentrated. Purification of theresidue on a silica gel column (0 to 50% EtOAc/hexanes) afforded4-(5-chloropyridin-3-yl)-6-(6-methoxypyridin-2-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine.MS ES calc'd. for C₃₅H₃₇ClN₆O₂ [M+H]⁺ 609, found 609.

Step 2: A mixture of4-(5-chloropyridin-3-yl)-6-(6-methoxypyridin-2-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine(63.0 mg, 0.104 mmol), p-toluenesulfonic acid monohydrate (198 mg, 1.04mmol), and lithium chloride (44.1 mg, 1.04 mmol) in DMA (1.0 mL) washeated at 100° C. for 24 hours under a nitrogen atmosphere. The reactionmixture was cooled to room temperature and diluted with water (10 mL).The reaction mixture was extracted with dichloromethane (3×10 mL). Thecombined organic layers were washed with water (2×10 mL), and brine (10mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, andconcentrated. Purification of the residue on a silica gel column (0 to10% CH₂Cl₂/MeOH) afforded6-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}pyridin-2(1H)-one.¹H NMR (400 MHz, CDCl₃) δ 10.69 (br s, 1H), 8.71 (d, J=2.4 Hz, 1H), 8.50(m, 1H), 8.02 (s, 1H), 7.86 (m, 1H), 7.50 (dd, J=9.0, 6.8 Hz, 1H),7.32-7.41 (m, 2H), 7.23-7.31 (m, 3H), 6.79-6.86 (m, 1H), 6.58 (d, J=9.0Hz, 1H), 4.66 (m, 1H), 4.08-4.14 (m, 2H), 3.92-4.07 (m, 2H), 3.62-3.74(m, 1H), 3.36-3.54 (m, 3H), 1.39-1.51 (m, 2H), 1.02-1.18 (m, 1H),0.80-0.94 (m, 1H), 0.75 (d, J=6.4 Hz, 3H), 0.55-0.71 (m, 4H), 0.36-0.52(m, 2H). MS ES calc'd. for C₃₄H₃₅ClN₆O₂ [M+H]⁺ 595, found 595.

Example 20.1 was prepared as described above.

TABLE 20 FRET [M + H]+ [M + H]+ Ex. IC₅₀ (nM) Structure Chemical NameSalt Calc'd Obsv'd 20.1 70

6-{4-(5-chloropyridin- 3-yl)-3-[(trans-4- methylcyclohexyl)methyl]-2-[(3R)-3- phenylmorpholin-4-yl]- 3H-imidazo[4,5-c]pyridin-6-yl}pyridin- 2(1H)-one 595 595

Example 21.13-{4-(cyclobutylmethoxy)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one

Step 1: To a solution of4,6-dichloro-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine(Example 2.1, Step 2; 400 mg, 0.87 mmol) in DMSO (5 mL) was addedcyclobutylmethanol (337 mg, 3.92 mmol), Cs₂CO₃ (848 mg, 2.61 mmol) andBINAP (108 mg, 0.17 mmol). The reaction mixture was deoxygenated bypurging with nitrogen for 10 minutes and then Pd₂ dba₃ (159 mg, 0.17mmol) was added. The reaction was again deoxygenated for 5 minutes bypurging with nitrogen. The reaction flask was sealed, and the mixturewas heated at 100° C. for 16 h. The reaction mixture was then cooled,diluted with water (30 ml) and EtOAc (60 mL), and the organic layer wasseparated. The organic layer was washed with water (2×10 mL), followedby saturated brine (2×30 mL). The organic layer was dried over anhydrousNa₂SO₄, filtered, and concentrated. The residue was purified on a silicagel column (30% EtOAc/petroleum ether) to yield6-chloro-4-(cyclobutylmethoxy)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine.MS ES/APCl calc'd. for C₂₉H₃₇ClN₄O₂ [M+H]⁺ 509, found 509.

Step 2: To a solution of6-chloro-4-(cyclobutylmethoxy)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine(120 mg, 0.23 mmol) in DMF (1.5 mL) was added Zn(CN)₂ (83 mg, 0.70mmol), and the mixture was deoxygenated by purging with nitrogen for 10minutes. Pd(dppf)Cl₂ dichloromethane adduct (57.7 mg, 0.07 mmol) wasadded and the reaction was again deoxygenated for 5 minutes. Thereaction flask was sealed and the mixture was heated at 140° C. for 16h. The reaction mixture was then cooled to room temperature, dilutedwith EtOAc (50 mL), and the organic layer was separated. The organiclayer was washed with water (2×50 mL) followed by saturated brinesolution (2×30 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated. The residue was purified by silica gel chromatography (40%EtOAc/petroleum ether) to yield4-(cyclobutylmethoxy)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.MS ES/APCl calc'd. for C₃₀H₃₇N₅O₂ [M+H]⁺ 500, found 500.

Steps 3 & 4: Using procedures similar to those described for Example 2.1(Steps 5 and 6),4-(cyclobutylmethoxy)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrilewas converted to3-{4-(cyclobutylmethoxy)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one.MS ES/APCl calc'd. for C₃₁H₃₈N₆O₄ [M+H]⁺ 559, found 559. ¹H NMR (400MHz, DMSO-d₆): δ 12.66 (s, 1H), 7.58 (s, 1H), 7.39-7.37 (m, 2H),7.24-7.15 (m, 3H), 4.60-4.54 (m, 2H), 4.43 (dd, J=6.7, 11.0 Hz, 1H),4.25-4.15 (m, 1H), 4.05-3.95 (m, 1H), 3.92-3.82 (m, 4H), 3.45-3.35 (m,1H), 3.12-3.05 (m, 1H), 2.80-2.73 (m, 1H), 2.12-2.09 (m, 2H), 1.96-1.85(m, 4H), 1.68-1.60 (m, 2H), 1.32-1.29 (m, 3H), 1.20-1.16 (m, 1H),1.01-0.99 (m, 2H), 0.84 (d, J=6.5 Hz, 3H), 0.80-0.77 (m, 2H).

Example 21.23-{4-(1-cyclobutylethoxy)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(mixture of diastereomers)

Step 1: To a stirred solution of 1-cyclobutylethan-1-ol (1.76 g, 17.60mmol) in DMF (10 mL) was added 60% NaH (1.4 g, 35.19 mmol) in severalportions at 0° C. After stirring for 20 minutes,4,6-dichloro-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine(Preparative Example 2.3, 3.5 g, 11.73 mmol) in DMF (30 mL) was addedslowly over a time period of 10 minutes. The reaction was then warmed toroom temperature and stirred for 16 h. After this time, the reaction wasquenched with ice, diluted with water (80 mL), and extracted with ethylacetate (3×30 mL). The combined organic extracts were washed with water(25 mL) and brine (25 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated. The residue was purified by silica gel chromatography(eluting with (12-15% EtOAc/petroleum ether) to yield6-chloro-4-(1-cyclobutylethoxy)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine.MS ES/APCl calc'd. for C₂₀1-1₂₈ClN₃O [M+H]⁺ 362, found 362.

Step 2: To a stirred solution of6-chloro-4-(1-cyclobutylethoxy)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine(3.5 g, 11.73 mmol) in THF (20 mL) was added2,2,6,6-tetramethylpiperidinyl magnesium chloride lithium chloridecomplex (1.0 M in THF/Toluene, 29.8 mL, 29.84 mmol) at −78° C. Theresulting solution was stirred 2.5 hours and then 1,3 dibromo-5,5dimethyl hydantoin (8.5 g, 29.84 mmol) in THF (20 mL) was added dropwiseat −78° C. The reaction was stirred for 30 minutes then slowly warmed toroom temperature over a period of 2 hours. The reaction was quenchedwith saturated NH₄Cl solution (50 mL) at 0° C. and extracted with EtOAc(2×20 mL). The combined organic extracts were washed with water (20 mL)and brine (20 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated. The residue was purified by silica gel chromatography(eluting with 8-10% EtOAc/petroleum ether) to yield2-bromo-6-chloro-4-(1-cyclobutylethoxy)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine.MS ES/APCl calc'd. for C₂₀H₂₇BrClN₃O [M+H]⁺ 440, found 440.

Step 3: To a solution of2-bromo-6-chloro-4-(1-cyclobutylethoxy)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine(1.5 g, 3.40 mmol) in DMSO (15 mL), in a microwave tube was added(R)-3-phenylmorpholine (797 mg, 4.77 mmol) and cesium fluoride (3.6 g,23.8 mmol). The reaction was heated at 125° C. in a microwave for 45mins. The reaction was then diluted with water (50 mL) and extractedwith ethyl acetate (2×30 mL). The combined organic extracts were washedwith water (20 mL) and brine (20 mL), dried over anhydrous Na₂SO₄,filtered, and concentrated. The residue was purified by silica gelchromatography (eluting with 8-10% EtOAc/petroleum ether) to yield(3R)-4-(6-chloro-4-(1-cyclobutylethoxy)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-2-yl)-3-phenylmorpholine.MS ES/APCl calc'd. for C₃₀H₃₉ClN₄O₂ [M+H]⁺ 523, found 523.

Steps 4-6: Following procedures similar to those described for Example21.1 (Step 2) and Example 2.1 (Steps 5 and 6),(3R)-4-(6-chloro-4-(1-cyclobutylethoxy)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-2-yl)-3-phenylmorpholinewas converted to3-{4-(1-cyclobutylethoxy)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one(mixture of diastereomers). ¹H-NMR (400 MHz, DMSO-d₆): δ 12.70 (s, 1H),7.56-7.55 (m, 1H), 7.40-7.37 (m, 2H), 7.24-7.15 (m, 3H), 5.72-5.65 (m,1H), 4.59 (d, J=6.8 Hz, 1H), 4.00-3.95 (m, 1H), 3.91-3.79 (m, 5H),3.12-3.10 (m, 1H), 2.60-2.55 (m, 1H), 2.01-1.94 (m, 7H), 1.83-1.80 (m,2H), 1.28-1.24 (m, 4H), 1.16 (d, J=6.0 Hz, 3H), 1.04-1.01 (m, 2H), 0.84(d, J=6.4 Hz, 3H), 0.81-0.75 (m, 2H). MS ES/APCl calc'd. for C₃₂H₄₀N₆O₄[M−H]⁺ 571, found 571.

Examples 21.1 and 21.2 were prepared as described above.

TABLE 21 FRET [M + H]+ [M + H]+ Ex. IC₅₀ (nM) Structure Chemical NameSalt Calc'd Obsv'd 21.1 37

3-{4- (cyclobutylmethoxy)-3- [(trans-4- methylcyclohexyl)methyl]-2-[(3R)-3- phenylmorpholin-4-yl]- 3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one 559 559 21.2 28

3-{4-(1- cyclobutylethoxy)-3- [(trans-4- methylcyclohexyl)methyl]-2-[(3R)-3- phenylmorpholin-4-yl]- 3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4- oxadiazol-5(4H)-one (mixture of diastereomers)571 [M − H] 571

Example 2 FRET Assay

Methods: An HDM2 FRET assay was developed to assess the compounds'inhibitory activity towards binding of p53 protein. A truncated versionof HDM2 with residues 17 to 125 (containing p53 binding surface, Science(1994) 265, 346-355), with N-terminal His and Thioredoxin tag wasgenerated in pET32a expression vector and expressed in E. coli strainBL21(DE3)Rosetta. Protein was purified using Ni-affinity chromatography,followed by size exclusion chromatography using Superdex 75 26/60column. To assess inhibition of p53 binding to HDM2, a FITC labeled8-mer peptide (SEQ ID NO:1:Ac-Phe-Arg-Dpr-Ac6c-(6-Br)Trp-Glu-Glu-Leu-NH₂; Anal Biochem. 2004 Aug.1; 331(1):138-46) with strong affinity towards the p53 binding pocket ofHDM2 was used. The HDM2 assay buffer contained 1× Phosphate BufferedSaline (Invitrogen, Cat#14190), 0.01% BSA (Jackson ImmunoResearch,Cat#001-000-162), 0.01% Tween-20. In the 1× assay buffer recombinantHDM2 protein, peptide and Lumi-4-Tb Cryptate-conjugate mouse anti-6×Hisantibody (cisbio, Cat# Tb61 HISTLB) were added and transferred toProxiPlate PLUS (PerkinElmer, Cat#6008269), containing compounds so thatfinal DMSO concentration is 0.1%. Final concentrations of reagents inthe assay wells are 0.5 nM HDM2, 0.25 nM anti HIS (Tb label) antibodyand 3 nM peptide. After two hour incubation at room temperature in ahumidified chamber plates were read on EnVision plate reader with thefollowing settings: excitation: UV, 340 nM, two emission filters: 520 nmand 495 nm respectively. Ratio of em520/em495 was used to calculate %inhibition and to obtain IC₅₀ with 4-parameter logistic equation.

IC₅₀ DETERMINATIONS: Dose-response curves were plotted from theinhibition data, from 10 point serial dilutions of inhibitory compounds.Concentration of compound was plotted against em520/Cem495 ratio signal.To generate IC₅₀ values, the dose-response curves were fitted to astandard sigmoidal curve and IC₅₀ values were derived by nonlinearregression analysis. IC₅₀ values in the above table are rounded to thenearest integer.

Example 3 Cell Viability Assay

Additionally, compounds can be tested for activity at the HDM2 proteinusing the Cell Viability Assay (SJSA-1 or HCT-116 cell line), whichmeasures the number of viable cells in culture after treatment with theinventive compound for a certain period of time e.g. 72 hours based onquantitation of the ATP present (Cell Viability. IC₅₀). [CellTiter-Glo®Luminescent Cell Viability Assay from Promega]. IC₅₀ of compounds of theexamples which values were determined in the SJSA-1 cell line rangedfrom 32 to 7963 nM. IC₅₀ of compounds of the examples which values weredetermined in the HCT-116 cell line ranged from 31 to 9866 nM.

1. A method of treating cancer in a patient comprising the step ofadministering to the patient an effective amount of a compound selectedfrom the group consisting of:

or a stereoisomer thereof; or a pharmaceutically acceptable saltthereof; or a pharmaceutically acceptable salt of the stereoisomerthereof.
 2. A method of treating cancer in a patient comprising the stepof administering to the patient an effective amount of a compoundselected from the group consisting of:

or a stereoisomer thereof; or a pharmaceutically acceptable saltthereof; or a pharmaceutically acceptable salt of the stereoisomerthereof.
 3. The method of claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 4. The method of claim 1,wherein the compound is

or a pharmaceutically acceptable salt thereof.
 5. The method of claim 1,wherein the compound is

or a pharmaceutically acceptable salt thereof.
 6. The method of claim 1,wherein the compound is

or a pharmaceutically acceptable salt thereof.
 7. The method of claim 1,wherein the compound is

or a pharmaceutically acceptable salt thereof.
 8. The method of claim 1,wherein the compound is

or a pharmaceutically acceptable salt thereof.
 9. The method of claim 1,wherein the compound is

or a pharmaceutically acceptable salt thereof.
 10. The method of claim1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 11. The method of claim1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 12. The method of claim1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 13. The method of claim1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 14. The method of claim1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 15. The method of claim1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 16. The method of claim1, wherein the cancer is selected from the group consisting of lymphoma,acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma,melanoma, sarcoma, liposarcoma, glioblastoma, colorectal cancer andcancer of the breast, stomach, prostate, endometrium, kidney, colon,ovary or lung.